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1. Emotional processes in partners’ quality of life at various stages of breast cancer pathway: a longitudinal study

Author: Anne-Sophie Baudry, Laurence Vanlemmens, Anne Congard, Aurélie Untas, Carine Segura-Djezzar, Claudia Lefeuvre-Plesse, Florence Coussy, Séverine Guiu, Jean-Sébastien Frenel, Baptiste Sauterey, Sonya Yakimova, Véronique Christophe, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Laboratoire de Psychologie des Pays de la Loire (LPPL), Université d'Angers (UA)-Nantes Université - UFR Lettres et Langages (Nantes Univ - UFR LL), Nantes Université - pôle Humanités, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Humanités, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Laboratoire de Psychopathologie et Processus de Santé (LPPS (URP_4057)), Université Paris Cité (UPCité), Department of Medical Oncology, CRLCC Eugène Marquis (CRLCC), Residual Tumor & Response to Treatment Laboratory [Paris] (RT2Lab), Translational Research Department [Paris], Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Oncologie Médicale [Institut Curie, Paris], Institut Curie [Paris], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Integrative Cancer Genomics (CRCI2NA / Eq 8), Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA ), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), Centre de Recherche en Psychologie de la Connaissance, du Langage et de l'Émotion (PsyCLÉ), Aix Marseille Université (AMU), Unité de Recherche en Sciences Cognitives et Affectives (URECA), and Université de Lille, Sciences Humaines et Sociales-PRES Université Lille Nord de France
Subjects: [SCCO.PSYC]Cognitive science/Psychology, Public Health, Environmental and Occupational Health
Abstract: Several studies have shown that emotional competence (EC) impacts cancer adjustment via anxiety and depression symptoms. The objective was to test this model for the quality of life (QoL) of partners: first, the direct effect of partners' EC on their QoL, anxiety and depression symptoms after cancer diagnosis (T1), after chemotherapy (T2) and after radiotherapy (T3); Second, the indirect effects of partners' EC at T1 on their QoL at T2 and T3 through anxiety and depression symptoms.192 partners of women with breast cancer completed a questionnaire at T1, T2 and T3 to assess their EC (PEC), anxiety and depression symptoms (HADS) and QoL (Partner-YW-BCI). Partial correlations and regression analyses were performed to test direct and indirect effects of EC on issues.EC at T1 predicted fewer anxiety and depression symptoms at each time and all dimensions of QoL, except for career management and financial difficulties. EC showed different significant indirect effects (i.e. via anxiety or depression symptoms) on all sub-dimensions of QoL, except for financial difficulties, according to the step of care pathway (T2 and T3). Anxiety and depression played a different role in the psychological processes that influence QoL.Findings confirm the importance of taking emotional processes into account in the adjustment of partners, especially regarding their QoL and the support they may provide to patients. It, thus, seems important to integrate EC in future health models and psychosocial interventions focused on partners or caregivers.
Published: 2022

2. Digital phenotyping in young breast cancer patients treated with neoadjuvant chemotherapy (the NeoFit Trial): protocol for a national, multicenter single-arm trial

Author: Lidia Delrieu, Anne-Sophie Hamy, Florence Coussy, Amyn Kassara, Bernard Asselain, Juliana Antero, Paul De Villèle, Elise Dumas, Nicolas Forstmann, Julien Guérin, Judicael Hotton, Christelle Jouannaud, Maud Milder, Armand Leopold, Adrien Sedeaud, Pauline Soibinet, Jean-François Toussaint, Vincent Vercamer, Enora Laas, Fabien Reyal, Residual Tumor & Response to Treatment Laboratory [Paris] (RT2Lab), Translational Research Department [Paris], Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Oncologie Médicale [Institut Curie, Paris], Institut Curie [Paris], Groupe d'Investigateurs Nationaux pour l'Étude des Cancers de l'Ovaire et du sein [Paris] (GINECO), Institut de recherche biomédicale et d’épidémiologie du sport (IRMES - URP_7329), Institut national du sport, de l'expertise et de la performance (INSEP)-Université Paris Cité (UPCité), Withings [Issy-les-Moulineaux] (W), Institut national du sport, de l'expertise et de la performance (INSEP), CRLCC Jean Godinot, Centre d'Investigation en Médecine du sport (CIMS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu, Département d'Oncologie Chirurgicale [Institut Curie], and Malbec, Odile
Subjects: Male, Cancer Research, Prevention, [SDV]Life Sciences [q-bio], Breast Neoplasms, Digital, Neoadjuvant Therapy, [SDV] Life Sciences [q-bio], Oncology, Antineoplastic Combined Chemotherapy Protocols, Quality of Life, Genetics, Humans, Multicenter Studies as Topic, Female, Prospective Studies, Neoadjuvant, Activity trackers
Abstract: Background Breast cancer (BC) has particular characteristics in young women, with diagnosis at more advanced stages, a poorer prognosis and highly aggressive tumors. In NeoFit, we will use an activity tracker to identify and describe various digital profiles (heart rate, physical activity, and sleep patterns) in women below the age of 45 years on neoadjuvant chemotherapy for BC. Methods NeoFit is a prospective, national, multicenter, single-arm open-label study. It will include 300 women below the age of 45 years treated with neoadjuvant chemotherapy for BC. Participants will be asked to wear a Withing Steel HR activity tracker round the clock for 12 months. The principal assessments will be performed at baseline, at the end of neoadjuvant chemotherapy and at 12 months. We will evaluate clinical parameters, such as toxicity and the efficacy of chemotherapy, together with quality of life, fatigue, and parameters relating to lifestyle and physical activity. The women will complete REDCap form questionnaires via a secure internet link. Discussion In this study, the use of an activity tracker will enable us to visualize changes in the lifestyle of young women on neoadjuvant chemotherapy for BC, over the course of a one-year period. This exploratory study will provide crucial insight into the digital phenotypes of young BC patients on neoadjuvant chemotherapy and the relationship between these phenotypes and the toxicity and efficacy of treatment. This trial will pave the way for interventional studies involving sleep and physical activity interventions. Trial registration Clinicaltrials.gov identifier: NCT05011721. Registration date: 18/08/2021.
Published: 2022

3. Adjustment of young women with breast cancer after chemotherapy: A mediation model of emotional competence via emotional distress

Author: Anne‐Sophie Baudry, Sonya Yakimova, Anne Congard, Aurélie Untas, Séverine Guiu, Claudia Lefeuvre‐Plesse, Catherine Loustalot, Cécile Guillemet, Carine Segura‐Djezzar, Aude‐Marie Savoye, Florence Coussy, Jean‐Sébastien Frenel, Laurence Vanlemmens, Véronique Christophe, Centre de Recherche en Psychologie de la Connaissance, du Langage et de l'Émotion (PsyCLÉ), Aix Marseille Université (AMU), Laboratoire de Psychologie des Pays de la Loire (LPPL), Université d'Angers (UA)-Nantes Université - UFR Lettres et Langages (Nantes Univ - UFR LL), Nantes Université - pôle Humanités, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Humanités, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Laboratoire de Psychopathologie et Processus de Santé (LPPS (URP_4057)), Université Paris Cité (UPCité), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), CRLCC Val d'Aurelle - Paul Lamarque, Centre Eugène Marquis (CRLCC), Centre hospitalier d'Auxerre (CHA), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Residual Tumor & Response to Treatment Laboratory [Paris] (RT2Lab), Translational Research Department [Paris], Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Oncologie Médicale [Institut Curie, Paris], Institut Curie [Paris], Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Laboratoire Sciences Cognitives et Sciences Affectives - UMR 9193 (SCALab), and Université de Lille-Centre National de la Recherche Scientifique (CNRS)
Subjects: Psychiatry and Mental health, Oncology, Depression, [SCCO.PSYC]Cognitive science/Psychology, Quality of Life, Humans, Breast Neoplasms, Female, Experimental and Cognitive Psychology, Anxiety, Child, Psychological Distress
Abstract: Emotional competence (EC) is considered a substantial resource in the adjustment of cancer patients, especially via its effect on anxiety and depression symptoms. This research aimed at assessing the impact of intrapersonal EC in young women (≤45 years) with breast cancer (YWBC) on their specific quality of life (i.e. subjective experience related to daily difficulties and perceived repercussions of the disease and treatments) related to chemotherapy, via anxiety and depression symptoms.Two hundred fifty YWBC from 24 French centers completed a self-reported questionnaire after diagnosis (T1) and after the chemotherapy phase (T2), comprising the Young Women Breast Cancer Inventory, the Profile of EC and the Hospital Anxiety and Depression Scale. The indirect effect of EC (T1) on subjective experience (T2) via anxiety and depression symptoms (T2) was tested using regressions and the Macro PROCESS.Emotional competence predicted fewer anxiety and depression symptoms at T1 and T2, and a better subjective experience at T2 via fewer anxiety and depression symptoms. Depression symptoms appeared to be a stronger mediator than anxiety symptoms on four dimensions (Support from close relatives, feeling of couple cohesion, body image and sexuality, management of children and everyday life), whereas anxiety symptoms appeared to be a stronger mediator on two dimensions (negative affectivity and apprehension about the future, deterioration of relationships).These results support the importance of developing psycho-affective interventions to reinforce the EC of YWBC during chemotherapy in order to facilitate the cognitive and emotional processes necessary for a better adjustment and subjective experience.
Published: 2022

4. Patterns of Sequelae in Women with a History of Localized Breast Cancer: Results from the French VICAN Survey

Author: Lidia Delrieu, Elise Dumas, Anne-Déborah Bouhnik, Pierre-Etienne Heudel, Fabien Reyal, Douae El Fatouhi, Florence Coussy, Baptiste Fournier, Hugo Noelle, Mauricette Michallet, Anne-Sophie Hamy, Guy Fagherazzi, E. Jacquet, Béatrice Fervers, Olivia Pérol, Marc-Karim Bendiane, Liacine Bouaoun, Centre Léon Bérard [Lyon], Residual Tumor & Response to Treatment Laboratory [Paris] (RT2Lab), Translational Research Department [Paris], Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre international de Recherche sur le Cancer (CIRC), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Gustave Roussy (IGR), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL), Centre de Bioinformatique (CBIO), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire [Grenoble] (CHU), Université Joseph Fourier - Grenoble 1 (UJF), Unité Ad Hoc INSERM 000008 'Radiations : Défense, Santé, Environnement' [Lyon] (Inserm U1296), Centre Léon Bérard [Lyon]-Service de Santé des Armées-Institut National de la Santé et de la Recherche Médicale (INSERM), Luxembourg Institute of Health (LIH), Malbec, Odile, Radiations : Défense, Santé, Environnement [Lyon] (Inserm UA8), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], and MINES ParisTech - École nationale supérieure des mines de Paris
Subjects: Cancer Research, Pediatrics, medicine.medical_specialty, [SDV]Life Sciences [q-bio], lcsh:RC254-282, Article, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, breast cancer, prevention, medicine, In patient, 030212 general & internal medicine, 10. No inequality, business.industry, Cancer, Cognition, Mean age, sequelae, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Latent class model, Current analysis, 3. Good health, [SDV] Life Sciences [q-bio], Lifestyle factors, Oncology, 030220 oncology & carcinogenesis, VICAN, business
Abstract: Simple Summary Breast cancer induces sequelae even years after diagnosis, but little is currently known about long-term sequelae patterns. This study aimed to (1) assess the evolution of the main sequelae and treatment two and five years after diagnosis in women with early-stage breast cancer, (2) explore patterns of sequelae associated with given sociodemographic, clinical, and lifestyle factors. Our results show that six main classes of sequelae were identified and remain constant over time except for fatigue and cognitive sequelae. The latent class analysis identified two main classes of sequelae (functional and esthetic patterns) and we have highlighted that different risk factors such as treatment, sociodemographic level, and physical activity level were associated with an increased risk of long-term sequelae. Abstract Breast cancer (BC) remains complex for women both physically and psychologically. The objectives of this study were to (1) assess the evolution of the main sequelae and treatment two and five years after diagnosis in women with early-stage breast cancer, (2) explore patterns of sequelae associated with given sociodemographic, clinical, and lifestyle factors. The current analysis was based on 654 localized BC patients enrolled in the French nationwide longitudinal survey “vie après cancer” VICAN (January–June 2010). Information about study participants was collected at enrollment, two and five years after diagnosis. Changes over time of the main sequelae were analyzed and latent class analysis was performed to identify patterns of sequelae related to BC five years after diagnosis. The mean age (±SD) of study participants at inclusion was 49.7 (±10.5) years old. Six main classes of sequelae were identified two years and five years post-diagnosis (functional, pain, esthetic, fatigue, psychological, and gynecological). A significant decrease was observed for fatigue (p = 0.03) and an increase in cognitive sequelae was reported (p = 0.03). Two latent classes were identified—functional and esthetic patterns. Substantial sequelae remain up to five years after BC diagnosis. Changes in patient care pathways are needed to identify BC patients at a high risk.
Published: 2021
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5. Adjuvant chemotherapy for breast cancer after preoperative chemotherapy: A propensity score matched analysis

Author: Florence Coussy, Fabien Reyal, Jean-Yves Pierga, Julie Labrosse, Anne-Sophie Hamy, Marie Osdoit, Enora Laas, Bodescot, Myriam, Department of Surgery [Paris], Institut Curie [Paris], Residual Tumor & Response to Treatment Laboratory [Paris] (RT2 Lab), Translational Research Department [Paris], Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Department of Medical Oncology [Paris]
Subjects: Oncology, Adjuvant Chemotherapy, medicine.medical_treatment, Cancer Treatment, Cohort Studies, 0302 clinical medicine, Medicine and Health Sciences, 030212 general & internal medicine, Multidisciplinary, Pharmaceutics, Hormonal Therapy, Middle Aged, Prognosis, 3. Good health, Surgical Oncology, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Cohort, Preoperative Period, Medicine, Female, Anatomy, Cohort study, medicine.drug, Research Article, Clinical Oncology, medicine.medical_specialty, Histology, Science, Radiation Therapy, Context (language use), Surgical and Invasive Medical Procedures, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Vinorelbine, Disease-Free Survival, 03 medical and health sciences, Cancer Chemotherapy, Breast cancer, Drug Therapy, [SDV.CAN] Life Sciences [q-bio]/Cancer, Diagnostic Medicine, Internal medicine, medicine, Chemotherapy, Humans, Propensity Score, Retrospective Studies, business.industry, Biology and Life Sciences, Retrospective cohort study, medicine.disease, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Propensity score matching, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Clinical Medicine, business
Abstract: International audience; Although identified to be at a higher risk of relapse, no consensus exists on the treatment of breast cancer (BC) patients with no pathological complete response after neoadjuvant chemotherapy (NAC). The benefit of adjuvant chemotherapy (ADJ) in this context has scarcely been studied. We evaluated the benefit of administrating adjuvant chemotherapy in a real life cohort of BC patients with invasive residual disease after NAC. 1199 female BC patients with T1-3NxM0 invasive tumors receiving NAC at Institut Curie from 2002 to 2012 were included in the analysis. 1061 had been treated by NAC only, whereas 138 had received additional adjuvant chemotherapy after NAC (FUN protocol: 5-FU-Vinorelbine). We compared disease-free survival (DFS) and overall survival (OS) rates between patients having received NAC only and patients having received NAC+ADJ. To ensure comparability of our populations, we used a propensity score (which defines the probability of treatment assignment conditional on observed baseline covariates) and matched each patient having received NAC+ADJ (n = 138) with a patient having received NAC only that had a similar propensity score value. Before propensity score matching, DFS and OS rates were significantly lower in the NAC+ADJ group compared to NAC only, after 3 years, 5 years and 10 years follow-up (p
Published: 2020

6. Shifting the Balance of Activating and Inhibitory Natural Killer Receptor Ligands on BRAFV600E Melanoma Lines with Vemurafenib

Author: Eric Pasmant, Brigitte Dréno, Houssem Benlalam, Marina Colombo, Antoine Toubert, Emmanuelle Fourmentraux-Neves, Frédéric Vély, Florence Faure, Fanny Bouquet, Ariel Savina, Marie-Françoise Avril, Sylvie Rusakiewicz, Laurence Zitvogel, Meriem Messaoudene, Anne Caignard, Alexandra Frazao, Eric Vivier, Alloimmunité-Autoimmunité-Transplantation (A2T), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Immunologie [AP-HM], Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut ROCHE [Boulogne-Billancourt], Roche S.A.S, Service de biochimie et de génétique moléculaire [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Dermatologie [CHU Cochin], This work was supported by Roche Pharmaceuticals, Fondation ARC, Institut National du Cancer (2011-PLBIO-06, for M. Colombo and E. Fourmentraux-Neves, and PAIR Melanoma 2013-066), Ligue Nationale Contre le Cancer (for M. Messaoudene), and Cancerop^ole Ile de France (for A. Frazao)., Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Alloimmunité-Autoimmunité-Transplantation ( A2T ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ), Immunologie des tumeurs et immunothérapie ( UMR 1015 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre d'Immunologie de Marseille - Luminy ( CIML ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Hôpital de la Conception [CHU - APHM] ( LA CONCEPTION ), Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers, CHU Cochin [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], and Bernardo, Elizabeth
Subjects: 0301 basic medicine, MAPK/ERK pathway, Cancer Research, NK Cell Lectin-Like Receptor Subfamily K, Melanoma, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Natural killer T cell, NKG2D, medicine.disease, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 3. Good health, 03 medical and health sciences, 030104 developmental biology, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cancer research, medicine, Receptor, Vemurafenib, neoplasms, V600E, medicine.drug
Abstract: Over 60% of human melanoma tumors bear a mutation in the BRAF gene. The most frequent mutation is a substitution at codon 600 (V600E), leading to a constitutively active BRAF and overactivation of the MAPK pathway. Patients harboring mutated BRAF respond to kinase inhibitors such as vemurafenib. However, these responses are transient, and relapses are frequent. Melanoma cells are efficiently lysed by activated natural killer (NK) cells. Melanoma cells express several stress-induced ligands that are recognized by activating NK-cell receptors. We have investigated the effect of vemurafenib on the immunogenicity of seven BRAF-mutated melanoma cells to NK cells and on their growth and sensitivity to NK-cell–mediated lysis. We showed that vemurafenib treatment modulated expression of ligands for two activating NK receptors, increasing expression of B7-H6, a ligand for NKp30, and decreasing expression of MICA and ULBP2, ligands for NKG2D. Vemurafenib also increased expression of HLA class I and HLA-E molecules, likely leading to higher engagement of inhibitory receptors (KIRs and NKG2A, respectively), and decreased lysis of vemurafenib-treated melanoma cell lines by cytokine-activated NK cells. Finally, we showed that whereas batimastat (a broad-spectrum matrix metalloprotease inhibitor) increased cell surface ULBP2 by reducing its shedding, vemurafenib lowered soluble ULBP2, indicating that BRAF signal inhibition diminished expression of both cell-surface and soluble forms of NKG2D ligands. Vemurafenib, inhibiting BRAF signaling, shifted the balance of activatory and inhibitory NK ligands on melanoma cells and displayed immunoregulatory effects on NK-cell functional activities. Cancer Immunol Res; 5(7); 582–93. ©2017 AACR.
Published: 2017

7. Inhibition of effector antigen-specific T cells by intradermal administration of heme oxygenase-1 inducers

Author: Julien Pogu, Philippe Blancou, Maud Maquigneau, Frédéric Brau, Séverine Remy, Thomas Simon, Ignacio Anegon, Sylvie Pogu, Jean-François Fonteneau, Gilles Blancho, Eliane Piaggio, Nicolas Poirier, Bernard Vanhove, Centre de Recherche en Transplantation et Immunologie ( U1064 Inserm - CRTI - CHU Nantes ), Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Center for Vascular and Inflammatory Diseases [Baltimore, USA], University of Maryland School of Medicine [Baltimore], Immuno-Endocrinologie Cellulaire et Moléculaire [Nantes] ( IECM ), Université de Nantes ( UN ) -Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique ( ONIRIS ) -Institut National de la Recherche Agronomique ( INRA ), Institut de pharmacologie moléculaire et cellulaire ( IPMC ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers, OSE Immunotherapeutics [Nantes], Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), ANR-10-IBHU-0005/10-IBHU-0005,CESTI (TSI-IHU),CESTI (TSI-IHU) ( 2010 ), ANR-11-LABX-0016/11-LABX-0016,IGO,Immunothérapies Grand Ouest ( 2011 ), ANR-10-IDEX-0001-02/10-IDEX-0001,PSL,PSL ( 2010 ), ANR-10-IDEX-0001-02/11-LABX-0043,DCBIOL,Biologie des cellules dendritiques ( 2010 ), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), University of Maryland School of Medicine, University of Maryland System-University of Maryland System, Immuno-Endocrinologie Cellulaire et Moléculaire [Nantes] (IECM), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation Progreffe, JDRF [5-2010-640], IMBIO network, Region Pays de la Loire, IHU-Cesti project, Investissements d'Avenir French, ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010), ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), Centre hospitalier universitaire de Nantes (CHU Nantes)-Faculté de Médecine d'Angers-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Centre National de la Recherche Scientifique (CNRS)-Hôpital Laennec-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôtel-Dieu de Nantes, Institut Curie-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-10-IBHU-0005/10-IBHU-0005,CESTI (TSI-IHU),CESTI (TSI-IHU)(2010), ANR-11-LABX-0016/11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), ANR-10-IDEX-0001-02/10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), ANR-10-IDEX-0001-02/11-LABX-0043,DCBIOL,Biologie des cellules dendritiques(2010), Bernardo, Elizabeth, Instituts Hospitalo-Universitaires B - Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU) - - CESTI (TSI-IHU)2010 - ANR-10-IBHU-0005 - IBHU - VALID, Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID, Initiative d'excellence - Paris Sciences et Lettres - - PSL2010 - ANR-10-IDEX-0001 - IDEX - VALID, Immuno-Endocrinologie Cellulaire et Moléculaire (IECM), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)-Ecole Nationale Vétérinaire de Nantes-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)
Subjects: CD4-Positive T-Lymphocytes, 0301 basic medicine, T-lymphocyte, Chemokine, T-Lymphocytes, T cell, Immunology, Antigen-Presenting Cells, Mice, Transgenic, T-Cell Antigen Receptor Specificity, [SDV.CAN]Life Sciences [q-bio]/Cancer, Autoimmunity, Autoantigens, Autoimmune Diseases, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Mice, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigen, medicine, Animals, Humans, Immunology and Allergy, Hypersensitivity, Delayed, Intradermal injection, Antigens, Migration, biology, Effector, Diabetes, Dendritic cell, Papio anubis, Auto-immune encephalomyelitis, Delayed type hypersensitivity, 3. Good health, Heme oxygenase, 030104 developmental biology, medicine.anatomical_structure, Gene Expression Regulation, Heme oxygenase-1, biology.protein, Cytokines, Immunization, Myelin-Oligodendrocyte Glycoprotein, Tolerance, Monocyte-derived dendritic cells, CD8, T-Lymphocytes, Cytotoxic
Abstract: International audience; Developing protocols aimed at inhibiting effector T cells would be key for the treatment of T cell-dependent autoimmune diseases including type 1 autoimmune diabetes (T1D) and multiple sclerosis (MS). While heme oxygenase-1 (HO-1) inducers are clinically approved drugs for non-immune-related diseases, they do have immunosuppressive properties when administered systemically in rodents. Here we show that HO-1 inducers inhibit antigen-specific effector T cells when injected intradermally together with the T cell cognate antigens in mice. This phenomenon was observed in both a CD8 þ T cell-mediated model of T1D and in a CD4 þ T cell-dependent MS model. Intradermal injection of HO-1 in-ducers induced the recruitment of HO-1 þ monocyte-derived dendritic cell (MoDCs) exclusively to the lymph nodes (LN) draining the site of intradermal injection. After encountering HO-1 þ MoDCs, effector T-cells exhibited a lower velocity and a reduced ability to migrate towards chemokine gradients resulting in impaired accumulation to the inflamed organ. Intradermal co-injection of a clinically approved HO-1 inducer and a specific antigen to non-human primates also induced HO-1 þ MoDCs to accumulate in dermal draining LN and to suppress delayed-type hypersensitivity. Therefore, in both mice and non-human primates, HO-1 inducers delivered locally inhibited effector T-cells in an antigen-specific manner, paving the way for repositioning these drugs for the treatment of immune-mediated diseases.
Published: 2017

8. Peripheral CD8 effector-memory type 1 T-cells correlate with outcome in ipilimumab-treated stage IV melanoma patients

Author: Christian U. Blank, Michele Maio, Michael A. Postow, Benjamin Weide, Phillip Wong, Dirk Schadendorf, Anna Maria Di Giacomo, Florian Heubach, Jianda Yuan, Paolo A. Ascierto, Amir Khammari, Marnix H Geukes Foppen, Brigitte Dréno, Graham Pawelec, Claus Garbe, Emanuela Romano, Domenico Mallardo, Bastian Schilling, Jedd D. Wolchok, Kilian Wistuba-Hamprecht, Alexander Martens, Department of Dermatology [Tubingen, Germany], University Medical Center [Tubingen, Germany], Department of Internal Medicine II [Tübingen, Germany], University Medical Center [Tübingen, Germany], Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), The Netherlands Cancer Institute [Amsterdam, The Netherlands], Memorial Sloane Kettering Cancer Center [New York], Weill Medical College of Cornell University [New York], Istituto Nazionale Tumori Fondazione Pascale [Naples, Italy], Department of Dermatology [Essen, Germany], University Hospital [Essen, Germany]-West German Cancer Center [Essen, Germany]-University Duisburg-Essen [Germany], German Cancer Consortium [Heidelberg] (DKTK), Division of Medical Oncology and Immunotherapy [Siena, Italy], University Hospital of Siena, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), School of Science and Technology [Nottingham, U.K.], Nottingham Trent University, Division of Cancer Studies [London, UK], King‘s College London, Parts of this study were funded by Bristol-Myers Squibb (Munich, Germany) to B Weide. Parts of this study were funded by the EU Seventh Framework Program ‘PRIAT’ (Profiling Responders In Antibody Therapies) grant agreement no 305309 to C Garbe. Parts of this study were funded by Deutsche Forschungsgemeinschaft DFG PA 361-22/1 to G. Pawelec., European Project: 305309,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,PRIAT(2012), Bernardo, Elizabeth, Profiling Responders In Antibody Therapies - PRIAT - - EC:FP7:HEALTH2012-11-01 - 2014-10-31 - 305309 - VALID, Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Memorial Sloan Kettering Cancer Center [New York, NY, USA], Weill Cornell Medical College [New York, NY, USA], German Cancer Consortium - DKTK [Heidelberg, Germany], Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ), Nottingham Trent University [U.K.], European Project : 305309,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,PRIAT ( 2012 ), and Universität Duisburg-Essen = University of Duisburg-Essen [Essen]-University Hospital [Essen, Germany]-West German Cancer Center [Essen, Germany]
Subjects: CD4-Positive T-Lymphocytes, Male, 0301 basic medicine, Oncology, Cancer Research, Skin Neoplasms, Programmed Cell Death 1 Receptor, Medizin, Kaplan-Meier Estimate, CD8-Positive T-Lymphocytes, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, Biomarker, Effector memory cells, Ipilimumab, Melanoma, Prognosis, medicine.diagnostic_test, Effector, Antibodies, Monoclonal, Middle Aged, Flow Cytometry, Peripheral, 030220 oncology & carcinogenesis, Biomarker (medicine), Female, medicine.drug, Adult, medicine.medical_specialty, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, Peripheral blood mononuclear cell, Article, Flow cytometry, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigens, Neoplasm, Internal medicine, Biomarkers, Tumor, medicine, Humans, Aged, business.industry, medicine.disease, 030104 developmental biology, Immunology, business, Immunologic Memory, CD8
Abstract: International audience; The role of the assessment of peripheral T-cell phenotypes in predicting overall survival (OS) after ipilimumab treatment is unclear. Here, we analysed mononuclear cells in the blood before and at different time points during treatment with ipilimumab in 137 late-stage melanoma patients. The proportions of baseline naïve and memory T-cells were measured by flow cytometry and correlated with OS, with an emphasis on PD-1 expression. High frequencies (>13%) of CD8 effector-memory type 1 (EM1) T-cells at baseline correlated with longer OS (p = 0.029) and higher clinical response rates (p = 0.01). The frequency of these EM1 cells and the M category had independent impacts on OS (hazard ratio = 1.5, p = 0.033; and hazard ratio = 1.9, p = 0.007). In contrast, high baseline frequencies of late stage-differentiated effector memory CD8 cells (>23.8%) were negatively associated with OS (p = 0.034) but did not correlate with clinical response. Following treatment, a decrease of CD8 cells from baseline to the time of the second drug dose and at later time points was strongly and consistently correlated with a high clinical response rate. Our observations thus suggest an important predictive role of baseline CD8 EM1 cells and changes in CD8 cells for clinical response of ipilimumab. Further validation of these biomarker candidates is warranted.
Published: 2017

9. Lenalidomide in combination with intravenous rituximab (revri) in relapsed/refractory primary cns lymphoma or primary intraocular lymphoma: a multicenter prospective '

Author: Ghesquieres, H. (Herve), Chevrier, M. (M.), Laadhari, M. (M.), Chinot, O. (O.), Choquet, S. (Sylvain), Molucon-Chabrot, C. (Cecile), Beauchesne, P. (P.), Gressin, R. (R.), Morschhauser, F. (Franck), Schmitt, A. (Anna), Gyan, E. (E.), Hoang-Xuan, K. (K.), Nicolas-Virelizier, E. (Emmanuelle), Cassoux, N. (N.), Touitou, V. (V.), Le Garff-Tavernier, M. (M.), Savignoni, A. (A.), Turbiez, I. (I.), Soumelis, V. (V.), Houillier, C. (C.), Soussain, C. (Carole), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Hôpital de la Timone [CHU - APHM] (TIMONE), CIC AP-HP (pitie-Salpetriere)/inserm, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d’Hématologie Biologique [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Centre Hospitalier Universitaire de Nancy (CHU Nancy), Centre Hospitalier Universitaire [Grenoble] (CHU), Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 (GRITA), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Bergonié [Bordeaux], UNICANCER, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Curie [Paris], Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Ophtalmologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Hématologie Biologique [CHU Pitié-Salpêtrière], Université de Lille, LillOA, CHU Lille, Université de Lille, Groupe de Recherche sur les formes Injectables et les Technologies Associées (GRITA) - EA 7365, Université Claude Bernard Lyon 1 [UCBL], Hôpital de la Timone [CHU - APHM] [TIMONE], Centre Hospitalier Universitaire de Nancy [CHU Nancy], Centre Hospitalier Universitaire [Grenoble] [CHU], Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 [GRITA], Centre Hospitalier Régional Universitaire de Tours [CHRU Tours], and Immunité et cancer [U932]
Subjects: [SDV] Life Sciences [q-bio], primary vitreoretinal lymphoma, relapse, lenalidomide, rituximab, primary CNS lymphoma, hemic and lymphatic diseases, [SDV]Life Sciences [q-bio]
Abstract: International audience; Primary central nervous system lymphomas (PCNSLs) are mainly diffuse large B-cell lymphomas (DLBCLs) of the non-germinal center B-cell (non-GCB) subtype. This study aimed to determine the efficacy of rituximab plus lenalidomide (R2) in DLBCL-PCNSL.Patients with refractory/relapsed (R/R) DLBCL-PCNSL or primary vitreoretinal lymphoma (PVRL) were included in this prospective phase II study. The induction treatment consisted of eight 28-day cycles of R2 (rituximab 375/m2 i.v. D1; lenalidomide 20 mg/day, D1-21 for cycle 1; and 25 mg/day, D1-21 for the subsequent cycles); in responding patients, the induction treatment was followed by a maintenance phase comprising 12 28-day cycles of lenalidomide alone (10 mg/day, D1-21). The primary end point was the overall response rate (ORR) at the end of induction (P0 = 10%; P1 = 30%).Fifty patients were included. Forty-five patients (PCNSL, N = 34; PVRL, N = 11) were assessable for response. The ORR at the end of induction was 35.6% (95% CI 21.9-51.2) in assessable patients and 32.0% (95% CI 21.9-51.2) in the intent-to-treat analysis, including 13 complete responses (CR)/unconfirmed CR (uCR; 29%) and 3 partial responses (PR; 7%). The best responses were 18 CR/uCR (40%) and 12 PR (27%) during the induction phase. The maintenance phase was started and completed by 18 and 5 patients, respectively. With a median follow-up of 19.2 months (range 1.5-31), the median progression-free survival (PFS) and overall survival (OS) were 7.8 months (95% CI 3.9-11.3) and 17.7 months (95% CI 12.9 to not reached), respectively. No unexpected toxicity was observed. The peripheral baseline CD4/CD8 ratio impacted PFS [median PFS = 9.5 months (95% CI, 8.1-14.8] for CD4/CD8 ≥ 1.6; median PFS = 2.8 months, [95% CI, 1.1-7.8) for CD4/CD8
Published: 2019

10. Assessing reliability of intra-tumor heterogeneity estimates from single sample whole exome sequencing data

Author: Hélène Bonsang-Kitzis, Benjamin Sadacca, Judith Abecassis, Fabien Reyal, Cécile Laurent, Jean-Philippe Vert, Anne-Sophie Hamy, Bodescot, Myriam, Residual Tumor & Response to Treatment Laboratory [Paris] (RT2Lab), Translational Research Department [Paris], Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Bioinformatique (CBIO), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Mathématiques de Toulouse UMR5219 (IMT), Université Toulouse Capitole (UT Capitole), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Département de chirurgie, Institut Curie [Paris], Google Brain, Paris, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), MINES ParisTech - École nationale supérieure des mines de Paris, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse 1 Capitole (UT1), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3)
Subjects: 0301 basic medicine, Epidemiology, Gene Identification and Analysis, Inference, Single sample, 0302 clinical medicine, Selective advantage, Medicine and Health Sciences, Exome, Exome sequencing, 0303 health sciences, Multidisciplinary, Cancer Risk Factors, Confounding, Squamous Cell Carcinomas, Prognosis, Head and Neck Tumors, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Medicine, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Algorithms, Research Article, DNA Copy Number Variations, Science, Genetic Causes of Cancer, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Computational biology, Biology, Research and Analysis Methods, Tumor heterogeneity, Carcinomas, Cancer prognosis, 03 medical and health sciences, Genetic Heterogeneity, Breast cancer, Head and Neck Squamous Cell Carcinoma, [SDV.CAN] Life Sciences [q-bio]/Cancer, Diagnostic Medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Computational Techniques, Exome Sequencing, medicine, Genetics, Humans, Molecular Biology Techniques, Molecular Biology, Mutation Detection, 030304 developmental biology, Genetic heterogeneity, Genome, Human, Squamous Cell Carcinoma of Head and Neck, Computational Pipelines, Robustness (evolution), Biology and Life Sciences, Cancers and Neoplasms, Computational Biology, medicine.disease, Head and neck squamous-cell carcinoma, Human genetics, 030104 developmental biology, Head and Neck Cancers, Urinary Bladder Neoplasms, Medical Risk Factors, Mutation, Somatic Mutation, Cloning
Abstract: Tumors are made of evolving and heterogeneous populations of cells which arise from successive appearance and expansion of subclonal populations, following acquisition of mutations conferring them a selective advantage. Those subclonal populations can be sensitive or resistant to different treatments, and provide information about tumor aetiology and future evolution. Hence, it is important to be able to assess the level of heterogeneity of tumors with high reliability for clinical applications.In the past few years, a large number of methods have been proposed to estimate intra-tumor heterogeneity from whole exome sequencing (WES) data, but the accuracy and robustness of these methods on real data remains elusive. Here we systematically apply and compare 6 computational methods to estimate tumor heterogeneity on 1,697 WES samples from the cancer genome atlas (TCGA) covering 3 cancer types (breast invasive carcinoma, bladder urothelial carcinoma, and head and neck squamous cell carcinoma), and two distinct input mutation sets. We observe significant differences between the estimates produced by different methods, and identify several likely confounding factors in heterogeneity assessment for the different methods. We further show that the prognostic value of tumor heterogeneity for survival prediction is limited in those datasets, and find no evidence that it improves over prognosis based on other clinical variables.In conclusion, heterogeneity inference from WES data on a single sample, and its use in cancer prognosis, should be considered with caution. Other approaches to assess intra-tumoral heterogeneity such as those based on multiple samples may be preferable for clinical applications.
Published: 2019

11. Dendritic cell–derived exosomes for cancer therapy

Author: Guido Kroemer, Jonathan M. Pitt, Laurence Zitvogel, Fabrice Andre, Sebastian Amigorena, Alexander M.M. Eggermont, Jean-Charles Soria, Institut Gustave Roussy (IGR), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Saclay, Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Immunité et cancer (U932), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), Apoptose, cancer et immunité (U848), Plateforme Métabolisme-Métabolome (IFR87), Université Paris-Sud - Paris 11 (UP11), Immunologie et Cancérologie Intégratives (CRC - Inserm U1138), Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Karolinska University Hospital [Stockholm], Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy ( IGR ), Immunologie des tumeurs et immunothérapie ( UMR 1015 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse ( U981 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Gustave Roussy ( IGR ) -Université Paris-Sud - Paris 11 ( UP11 ), Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] ( DITEP ), Apoptose, cancer et immunité ( U848 ), Plateforme Métabolisme-Métabolome ( IFR87 ), Université Paris-Sud - Paris 11 ( UP11 ), Immunologie et Cancérologie Intégratives ( CRC - Inserm U1138 ), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Centre d'Investigation Clinique en Biotherapie des cancers ( CIC 1428 , CBT 507 ), and Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: 0301 basic medicine, endocrine system, T-Lymphocytes, medicine.medical_treatment, Cell, Cancer therapy, [SDV.CAN]Life Sciences [q-bio]/Cancer, chemical and pharmacologic phenomena, Exosomes, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Clinical Trials, Phase II as Topic, 0302 clinical medicine, Immune system, Immunity, Neoplasms, polycyclic compounds, medicine, Animals, Humans, Immunity, Cellular, Clinical Trials, Phase I as Topic, business.industry, Review Series, Cancer, Dendritic Cells, General Medicine, Immunotherapy, Dendritic cell, medicine.disease, Microvesicles, 3. Good health, Killer Cells, Natural, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, business, hormones, hormone substitutes, and hormone antagonists
Abstract: International audience; DC-derived exosomes (Dex) are nanometer-sized membrane vesicles that are secreted by the sentinel antigen-presenting cells of the immune system: DCs. Like DCs, the molecular composition of Dex includes surface expression of functional MHC-peptide complexes, costimulatory molecules, and other components that interact with immune cells. Dex have the potential to facilitate immune cell–dependent tumor rejection and have distinct advantages over cell-based immunotherapies involving DCs. Accordingly, Dex-based phase I and II clinical trials have been conducted in advanced malignancies, showing the feasibility and safety of the approach, as well as the propensity of these nanovesicles to mediate T and NK cell–based immune responses in patients. This Review will evaluate the interactions of Dex with immune cells, their clinical progress, and the future of Dex immunotherapy for cancer.
Published: 2016

12. Lyn and Fyn function as molecular switches that control immunoreceptors to direct homeostasis or inflammation

Author: Sanae Ben, Mkaddem, Amaya, Murua, Héloise, Flament, Dimitri, Titeca-Beauport, Carine, Bounaix, Luca, Danelli, Pierre, Launay, Marc, Benhamou, Ulrich, Blank, Eric, Daugas, Nicolas, Charles, Renato C, Monteiro, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Immunopathologie rénale, récepteurs et inflammation, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition ( ICAN ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP], Centre de recherche sur l'Inflammation ( CRI ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) ( HOTE GREFFON ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Université de Franche-Comté ( UFC ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), and Ben Mkaddem, Sanae
Subjects: Inflammation, Male, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Science, hemic and immune systems, Proto-Oncogene Proteins c-fyn, environment and public health, Mice, Inbred C57BL, Mice, enzymes and coenzymes (carbohydrates), src-Family Kinases, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, embryonic structures, Animals, Homeostasis, Humans, Female, Phosphorylation, biological phenomena, cell phenomena, and immunity, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Signal Transduction
Abstract: Immunoreceptors can transduce either inhibitory or activatory signals depending on ligand avidity and phosphorylation status, which is modulated by the protein kinases Lyn and Fyn. Here we show that Lyn and Fyn control immune receptor signaling status. SHP-1 tyrosine 536 phosphorylation by Lyn activates the phosphatase promoting inhibitory signaling through the immunoreceptor. By contrast, Fyn-dependent phosphorylation of SHP-1 serine 591 inactivates the phosphatase, enabling activatory immunoreceptor signaling. These SHP-1 signatures are relevant in vivo, as Lyn deficiency exacerbates nephritis and arthritis in mice, whereas Fyn deficiency is protective. Similarly, Fyn-activating signature is detected in patients with lupus nephritis, underlining the importance of this Lyn-Fyn balance. These data show how receptors discriminate negative from positive signals that respectively result in homeostatic or inflammatory conditions.Src-family kinases Fyn and Lyn are signaling components downstream of ITAM-bearing antigen receptors. Here the authors show that by phosphorylating SHP-1 at different residues, Lyn and Fyn can have opposing regulatory effects on ITAM receptors.
Published: 2017

13. Evolution of synchronous female bilateral breast cancers and response to treatment

Author: Anne-Sophie Hamy, Judith Abécassis, Keltouma Driouch, Lauren Darrigues, Mathias Vandenbogaert, Cecile Laurent, Francois Zaccarini, Benjamin Sadacca, Myriam Delomenie, Enora Laas, Odette Mariani, Thanh Lam, Beatriz Grandal, Marick Laé, Ivan Bieche, Sophie Vacher, Jean-Yves Pierga, Etienne Brain, Celine Vallot, Judicael Hotton, Wilfrid Richer, Dario Rocha, Zakia Tariq, Veronique Becette, Didier Meseure, Laetitia Lesage, Anne Vincent-Salomon, Natalie Filmann, Jenny Furlanetto, Sibylle Loibl, Elise Dumas, Joshua J. Waterfall, Fabien Reyal, Residual Tumor & Response to Treatment Laboratory [Paris] (RT2Lab), Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Modèles et inférence pour les données de Neuroimagerie (MIND), IFR49 - Neurospin - CEA, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Méthodes computationnelles et mathématiques pour comprendre la société et la santé à partir de données (SODA), Inria Saclay - Ile de France, Département de chirurgie, Département de Recherche Translationnelle, Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Departement de chirurgie [Institut Curie], Geneva University Hospitals and Geneva University, Département de Pathologie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Dynamique de l'information génétique : bases fondamentales et cancer (DIG CANCER), Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Jean Godinot [Reims], UNICANCER, and German Breast Group (GBG)
Subjects: [SDV]Life Sciences [q-bio], General Medicine, General Biochemistry, Genetics and Molecular Biology
Abstract: Synchronous bilateral breast cancer (sBBC) occurs after both breasts have been affected by the same germline genetics and environmental exposures. Little evidence exists regarding immune infiltration and response to treatment in sBBCs. Here we show that the impact of the subtype of breast cancer on levels of tumor infiltrating lymphocytes (TILs, n = 277) and on pathologic complete response (pCR) rates (n = 140) differed according to the concordant or discordant subtype of breast cancer of the contralateral tumor: luminal breast tumors with a discordant contralateral tumor had higher TIL levels and higher pCR rates than those with a concordant contralateral tumor. Tumor sequencing revealed that left and right tumors (n = 20) were independent regarding somatic mutations, copy number alterations and clonal phylogeny, whereas primary tumor and residual disease were closely related both from the somatic mutation and from the transcriptomic point of view. Our study indicates that tumor-intrinsic characteristics may have a role in the association of tumor immunity and pCR and demonstrates that the characteristics of the contralateral tumor are also associated with immune infiltration and response to treatment.
Published: 2023

14. Functional specialization of short-lived and long-lived macrophage subsets in human tonsils

Author: Lamine Alaoui, Javiera Villar, Renaud Leclere, Simon Le Gallou, Francis Relouzat, Henri-Alexandre Michaud, Karin Tarte, Natacha Teissier, Benoît Favier, Mikaël Roussel, Elodie Segura, Institut Curie [Paris], Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), CRLCC Val d'Aurelle - Paul Lamarque, Hôpital Robert Debré, Institut National de la Santé et de la Recherche Médicale, CIC IGR-Curie 1428, Institut Curie, ANR-10-LABX-0043, Agence Nationale de la Recherche, 2018-1-PL BIO-01-1, Institut National du Cancer, PJA 20171206249, Fondation ARC pour la Recherche sur le Cancer, 730964, TRANSVAC2 H2020, 666003, ERC Horizon 2020-Marie Sklodowska-Curie Actions, and FDT202106013025, Fondation pour la Recherche Médicale
Subjects: Immunology, Immunology and Allergy, [SDV.CAN]Life Sciences [q-bio]/Cancer
Abstract: International audience; Macrophages play a central role in tissue homeostasis and host defense. However, the properties of human macrophages in non-diseased tissues remain poorly understood. Here, we characterized human tonsil macrophages and identified three subsets with distinct phenotype, transcriptome, life cycle, and function. CD36hi macrophages were related to monocytes, while CD36lo macrophages showed features of embryonic origin and CD36int macrophages had a mixed profile. scRNA-seq on non-human primate tonsils showed that monocyte recruitment did not pre-exist an immune challenge. Functionally, CD36hi macrophages were specialized for stimulating T follicular helper cells, by producing Activin A. Combining reconstruction of ligand-receptor interactions and functional assays, we identified stromal cell-derived TNF-α as an inducer of Activin A secretion. However, only CD36hi macrophages were primed for Activin A expression, via the activity of IRF1. Our results provide insight into the heterogeneity of human lymphoid organ macrophages and show that tonsil CD36hi macrophage specialization is the result of both intrinsic features and interaction with stromal cells.
Published: 2023

15. Different TCR-induced T lymphocyte responses are potentiated by stiffness with variable sensitivity

Author: Nathalie Bufi, Atef Asnacios, Christel Goudot, Sophie Asnacios, Mathieu Maurin, Clotilde Randriamampita, Michael Saitakis, Claire Hivroz, Stéphanie Dogniaux, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Matière et Systèmes Complexes (MSC (UMR_7057)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), UPMC - Faculté de Physique (UFR 925), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Matière et Systèmes Complexes (MSC), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), This work was also supported by funds from Fondation pour la Recherche Médicale (FRM, FRM DEQ20140329513)., ANR-12-BSV5-0007,ImmunoMeca,Caractérisation du rôle de la mécanique dans l'immunité: vers un modèle intégré de l'activation des cellules T(2012), ANR-13-BSV2-0018,NeuroImmunoSynapse,Trafic vésiculaire, formation et maintien des synapses neuronales et immunologiques(2013), ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), ANR-11-LABX-0043,DCBIOL,Biologie des cellules dendritiques(2011), ANR-11-LABX-0071,WHO AM I,Determinants de l'Identité : de la molécule à l'individu(2011), This work was supported by funds from ANR (ANR-12-BSV5-0007-01, ImmunoMeca, ANR-13-BSV2-0018 ‘NeuroImmunoSynapse’), DC-Biol Labex (ANR-10-IDEX-0001–02 PSL* and ANR-11-LABX-0043), ‘Who Am I?’ Labex (ANR-11-IDEX-0005–02 and ANR-11-LABX-0071) and Fondation pour la Recherche Me´ dicale (FRM, FRM DEQ20140329513)., Hivroz, Claire, BLANC - Caractérisation du rôle de la mécanique dans l'immunité: vers un modèle intégré de l'activation des cellules T - - ImmunoMeca2012 - ANR-12-BSV5-0007 - BLANC - VALID, Blanc 2013 - Trafic vésiculaire, formation et maintien des synapses neuronales et immunologiques - - NeuroImmunoSynapse2013 - ANR-13-BSV2-0018 - Blanc 2013 - VALID, Initiative d'excellence - Paris Sciences et Lettres - - PSL2010 - ANR-10-IDEX-0001 - IDEX - VALID, Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID, HAL UPMC, Gestionnaire, Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire Matière et Systèmes Complexes ( Laboratoire MSC ), Université Paris Diderot - Paris 7 ( UPD7 ) -UFR de Physique, Faculté de Physique (UPMC) ( UFR 925 ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), [Institut Cochin] Departement Infection, immunité, inflammation, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), CNRS UMR 7057 - Laboratoire Matières et Systèmes Complexes (MSC) (MSC), and Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, CD4-Positive T-Lymphocytes, [SDV]Life Sciences [q-bio], Cell, [ SDV.IMM.IA ] Life Sciences [q-bio]/Immunology/Adaptive immunology, 0302 clinical medicine, biophysics, T lymphocyte, structural biology, Biology (General), ComputingMilieux_MISCELLANEOUS, Cells, Cultured, General Neuroscience, Stiffness, General Medicine, musculoskeletal system, Biophysics and Structural Biology, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, rigidity, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines, medicine.symptom, TCR, Research Article, Human, musculoskeletal diseases, animal structures, [SDV.IMM] Life Sciences [q-bio]/Immunology, QH301-705.5, T cell, Science, Immunology, Receptors, Antigen, T-Cell, macromolecular substances, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Immune system, medicine, Humans, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Mechanical Phenomena, General Immunology and Microbiology, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, T-cell receptor, technology, industry, and agriculture, equipment and supplies, 030104 developmental biology, Structural biology, Stress, Mechanical, Tissue stiffness, 030217 neurology & neurosurgery
Abstract: T cells are mechanosensitive but the effect of stiffness on their functions is still debated. We characterize herein how human primary CD4+ T cell functions are affected by stiffness within the physiological Young’s modulus range of 0.5 kPa to 100 kPa. Stiffness modulates T lymphocyte migration and morphological changes induced by TCR/CD3 triggering. Stiffness also increases TCR-induced immune system, metabolism and cell-cycle-related genes. Yet, upon TCR/CD3 stimulation, while cytokine production increases within a wide range of stiffness, from hundreds of Pa to hundreds of kPa, T cell metabolic properties and cell cycle progression are only increased by the highest stiffness tested (100 kPa). Finally, mechanical properties of adherent antigen-presenting cells modulate cytokine production by T cells. Together, these results reveal that T cells discriminate between the wide range of stiffness values found in the body and adapt their responses accordingly. DOI: http://dx.doi.org/10.7554/eLife.23190.001, eLife digest Our immune system contains many cells that play various roles in defending the body against infection, cancer and other threats. For example, T cells constantly patrol the body ready to detect and respond to dangers. They do so by gathering cues from their surroundings, which can be specific chemical signals or physical properties such as the stiffness of tissues. Once the T cells are active they respond in several different ways including releasing hormones and dividing to produce more T cells. Tissue stiffness varies considerably between different organs. Furthermore, disease can lead to changes in tissue stiffness. For example, tissues become more rigid when they are inflamed. The stiffness and other physical properties of the surfaces that T cells interact with affect how the cells respond when they detect a threat, but few details are known about exactly how these cues tune T cell responses. Saitakis et al. studied how human T cells respond to artificial surfaces of varying stiffness that mimic the range found in the body. The experiments show that T cells that interact with stiff surfaces become more active than T cells that interact with softer surfaces. However, some responses are more sensitive to the stiffness of the surface than others. For example, the ability of the T cells to release hormones was affected by the whole range of stiffnesses tested in the experiments, whereas only very stiff surfaces stimulated the T cells to divide. These findings show that T cells can detect the stiffness of surfaces in the body and use this to adapt how they respond to threats. Future challenges will be to find out how T cells sense the physical properties of their surroundings and investigate whether cell and tissue stiffness affects immune responses in the body. This will help us to understand how T cells fight infections and other threats, and could be used to develop new ways of boosting these cells to fight cancer and other diseases. DOI: http://dx.doi.org/10.7554/eLife.23190.002
Published: 2017

16. Standardized whole blood stimulation improves immunomonitoring of induced immune responses in multi-center study

Author: Alain Savenay, Matthew L. Albert, Delphine Louis, Manfred Schmolz, Nina Salabert-Le Guen, Olivier Lantz, Régis Josien, Darragh Duffy, Françoise Mascart, Antoine Toubert, Marie Noelle Ungeheuer, Vincent Rouilly, Raouf Djebali, Lydia Redjah, José J.G. Ruiz de Morales, Catherine Ottone, Véronique Corbière, Eva Martínez-Cáceres, Cécile Braudeau, Samuel S.T. LaBrie, Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle (CRT), Institut Pasteur [Paris], Laboratoire d’Immunologie, Centre d’Immunomonitorage Nantes Atlantique (CIMNA), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), laboratoire de vaccinologie et immunité mucosale, Université Libre de Bruxelles [Bruxelles] (ULB), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Myriad RBM, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospital Universitari Germans Trias I Pujol, Immunobiology Clinic, Hôpital Erasme, Complejo Asistencial Universitario de León, Alloimmunité-Autoimmunité-Transplantation (A2T), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), HOT Screen GmbH, Genentech, Inc. [San Francisco], TruCulture tubes, stimuli, and protein Luminex XMAP analysis were provided by Myriad RBM, Inc (Austin, USA) and TruCulture tubes were manufactured at HOT Screen (Reutlingen, Germany). Donor recruitment costs were covered by each participating FOCIS center of excellence. Author contributions: DD, VR, VC, SL, OL, EMC, RP, MS, AT & MLA designed the study. CB, RD, MNU, DL, FM, JGRM, CO, LR, AS performed experiments. DD, VR, & MLA performed analysis and wrote the paper. All authors reviewed the manuscript., Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Université libre de Bruxelles (ULB), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche Translationnelle ( CRT ), Centre Hospitalier Universitaire de Nantes, Centre de Recherche en Transplantation et Immunologie ( U1064 Inserm - CRTI - CHU Nantes ), Université de Nantes ( UN ) -Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Université Libre de Bruxelles [Bruxelles] ( ULB ), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources ( ICAReB ), Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Curie, Alloimmunité-Autoimmunité-Transplantation ( A2T ), and Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: 0301 basic medicine, Lipopolysaccharides, Whole blood stimulation, CD3 Complex, medicine.medical_treatment, CD8 Antigens, Point-of-Care Systems, Immunology, Stimulation, Blood Donors, Immunologic Tests, Peripheral blood mononuclear cell, Antibodies, Functional immune responses, 03 medical and health sciences, Immune system, medicine, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Immunology and Allergy, Humans, Whole blood, biology, business.industry, Immunotherapy, Multi-center clinical studies, 3. Good health, Vaccination, Immunomonitoring, 030104 developmental biology, Gene Expression Regulation, PBMCs, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines, Antibody, business, Biomarkers
Abstract: Functional immune responses are increasingly important for clinical studies, providing in depth biomarker information to assess immunotherapy or vaccination. Incorporating functional immune assays into routine clinical practice has remained limited due to challenges in standardizing sample preparation. We recently described the use of a whole blood syringe-based system, TruCulture (R), which permits point-of-care standardized immune stimulation. Here, we report on a multi-center clinical study in seven FOCIS Centers of Excellence to directly compare TruCulture to conventional PBMC methods. Whole blood and PBMC5 from healthy donors were exposed to LPS, anti-CD3 anti-CD28 antibodies, or media alone. 55 protein analytes were analyzed centrally by Luminex multi-analyte profiling in a CLIA-certified laboratory. TruCulture responses showed greater reproducibility and improved the statistical power for monitoring differential immune response activation. The use of TruCulture addresses a major unmet need through a robust and flexible method for immunomonitoring that can be reproducibly applied in multi-center clinical studies. One sentence summary: A multi-center study revealed greater reproducibility from whole blood stimulation systems as compared to PBMC stimulation for studying induced immune responses. (C) 2017 Published by Elsevier Inc.
Published: 2017

17. Phenotype of NK-Like CD8(+) T Cells with Innate Features in Humans and Their Relevance in Cancer Diseases

Author: Barbarin, Alice, Cayssials, Emilie, Jacomet, Florence, Nunez, Nicolas Gonzalo, Basbous, Sara, Lefèvre, Lucie, Abdallah, Myriam, Piccirilli, Nathalie, Morin, Benjamin, Lavoue, Vincent, Catros, Véronique, Piaggio, Eliane, Herbelin, André, Gombert, Jean-Marc, Jonchère, Laurent, Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Gynécologie et Obstétrique [Rennes] = Gynaecology [Rennes], CHU Pontchaillou [Rennes], Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), INSERM, CHU de Poitiers, Universite de Poitiers, Ligue contre le Cancer du Grand Ouest, Association pour la Recherche en Immunologic-Poitou-Charentes (ARIM-PC), les Regions Aquitaine Limousin Poitou-Charentes, Bretagne, Centre et Pays de la Loire (PlasTICO project), Association Laurette Fugain, Ministers de la Recherche, Sport and Collection, INCa-DGOS [8658, 2015-052], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT ), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Gynécologie et Obstétrique [Rennes], Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -CHU Pontchaillou [Rennes]-Hôpital Sud, Chemistry, Oncogenesis, Stress and Signaling ( COSS ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -CRLCC Eugène Marquis ( CRLCC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, innate memory cd8(+) t cells, natural killer receptors, [ SDV.AEN ] Life Sciences [q-bio]/Food and Nutrition, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, eomesodermin, [SDV.CAN] Life Sciences [q-bio]/Cancer, chronic myeloid leukemia, Hypothesis and Theory, inkt cells, nk-like t cells, cd49d, solid cancers, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: International audience; Unconventional T cells are defined by their capacity to respond to signals other than the well-known complex of peptides and major histocompatibility complex proteins. Among the burgeoning family of unconventional T cells, innate-like CD8(+) T cells in the mouse were discovered in the early 2000s. This subset of CD8(+) T cells bears a memory phenotype without having encountered a foreign antigen and can respond to innate-like IL-12 + IL-18 stimulation. Although the concept of innate memory CD8(+) T cells is now well established in mice, whether an equivalent memory NK-like T-cell population exists in humans remains under debate. We recently reported that CD8(+) T cells responding to innate-like IL-12 + IL-18 stimulation and co-expressing the transcription factor Eomesodermin (Eomes) and KIR/NKG2A membrane receptors with a memory/EMRA phenotype may represent a new, functionally distinct innate T cell subset in humans. In this review, after a summary on the known innate CD8(+) T-cell features in the mouse, we propose Eomes together with KIR/NKG2A and CD49d as a signature to standardize the identification of this innate CD8(+) T-cell subset in humans. Next, we discuss IL-4 and IL-15 involvement in the generation of innate CD8(+) T cells and particularly its possible dependency on the promyelocytic leukemia zinc-finger factor expressing iNKT cells, an innate T cell subset well documented for its susceptibility to tumor immune subversion. After that, focusing on cancer diseases, we provide new insights into the potential role of these innate CD8(+) T cells in a physiopathological context in humans. Based on empirical data obtained in cases of chronic myeloid leukemia, a myeloproliferative syndrome controlled by the immune system, and in solid tumors, we observe both the possible contribution of innate CD8(+) T cells to cancer disease control and their susceptibility to tumor immune subversion. Finally, we note that during tumor progression, innate CD8(+) T lymphocytes could be controlled by immune checkpoints. This study significantly contributes to understanding of the role of NK-like CD8(+) T cells and raises the question of the possible involvement of an iNKT/innate CD8(+) T cell axis in cancer.
Published: 2017

18. Enhancing the clinical coverage and anticancer efficacy of immune checkpoint blockade through manipulation of the gut microbiota

Author: Mathias Chamaillard, Marie Vétizou, Patricia Lepage, Ivo G. Boneca, Laurence Zitvogel, Jonathan M. Pitt, Institut Gustave Roussy (IGR), Université Paris-Sud 11 - Faculté de médecine (UP11 UFR Médecine), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Saclay, Equipe Avenir, Institut National de la Santé et de la Recherche Médicale (INSERM), Biology and genetics of the bacterial cell wall Unit, Institut Pasteur de Madagascar, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, Réseau International des Instituts Pasteur (RIIP), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunité et cancer (U932), Institut Curie-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy ( IGR ), Université Paris-Sud 11 - Faculté de médecine ( UP11 UFR Médecine ), Immunologie des tumeurs et immunothérapie ( UMR 1015 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), MICrobiologie de l'ALImentation au Service de la Santé humaine ( MICALIS ), Institut National de la Recherche Agronomique ( INRA ) -AgroParisTech, Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - UMR 8204 ( CIIL ), Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR142-Université de Lille-Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Régional Universitaire de Lille ( CHRU de Lille ), Réseau International des Instituts Pasteur ( RIIP ), Centre d'Investigation Clinique en Biotherapie des cancers ( CIC 1428 , CBT 507 ), Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Curie, Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, T cell, [SDV]Life Sciences [q-bio], Immunology, microbiome, Ipilimumab, chemical and pharmacologic phenomena, Gut flora, Anti-CTLA-4, 03 medical and health sciences, 0302 clinical medicine, medicine, microbiota, Immunology and Allergy, Bacteroides, cancer, Microbiome, ipilimumab, Adverse effect, Author's View, biology, [ SDV ] Life Sciences [q-bio], biology.organism_classification, Immune checkpoint, 3. Good health, Blockade, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, medicine.drug
Abstract: Although anticancer therapy with immune checkpoint blockers has seen unprecedented success, it fails to control neoplasia in most patients and often causes immune-related adverse events (irAEs). Our recent research shows the immunostimulatory and antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species of the gut microbiota, signifying novel approaches to improve such immunotherapies.
Published: 2017

19. ETV3 and ETV6 enable monocyte differentiation into dendritic cells by repressing macrophage fate commitment

Author: Javiera Villar, Adeline Cros, Alba De Juan, Lamine Alaoui, Pierre-Emmanuel Bonte, Colleen M. Lau, Ioanna Tiniakou, Boris Reizis, Elodie Segura, Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), New York University School of Medicine (NYU Grossman School of Medicine), ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), ANR-10-LABX-0043,BRAIN,Bordeaux Region Aquitaine Initiative for Neuroscience(2010), ANR-17-CE15-0011,MonoDiff,Régulation moléculaire de la différenciation des monocytes : des mécanismes aux cibles thérapeutiques(2017), European Project: 666003,H2020,H2020-MSCA-COFUND-2014,IC-3i-PhD(2016), Segura, Elodie, Initiative d'excellence - Paris Sciences et Lettres - - PSL2010 - ANR-10-IDEX-0001 - IDEX - VALID, Bordeaux Region Aquitaine Initiative for Neuroscience - - BRAIN2010 - ANR-10-LABX-0043 - LABX - VALID, Régulation moléculaire de la différenciation des monocytes : des mécanismes aux cibles thérapeutiques - - MonoDiff2017 - ANR-17-CE15-0011 - AAPG2017 - VALID, and Institut Curie 3-i PhD Program - IC-3i-PhD - - H20202016-09-01 - 2021-09-01 - 666003 - VALID
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], Immunology, Immunology and Allergy
Abstract: In inflamed tissues, monocytes differentiate into macrophages (mo-Macs) or dendritic cells (mo-DCs). In chronic nonresolving inflammation, mo-DCs are major drivers of pathogenic events. Manipulating monocyte differentiation would therefore be an attractive therapeutic strategy. However, how the balance of mo-DC versus mo-Mac fate commitment is regulated is not clear. In the present study, we show that the transcriptional repressors ETV3 and ETV6 control human monocyte differentiation into mo-DCs. ETV3 and ETV6 inhibit interferon (IFN)-stimulated genes; however, their action on monocyte differentiation is independent of IFN signaling. Instead, we find that ETV3 and ETV6 directly repress mo-Mac development by controlling MAFB expression. Mice deficient for Etv6 in monocytes have spontaneous expression of IFN-stimulated genes, confirming that Etv6 regulates IFN responses in vivo. Furthermore, these mice have impaired mo-DC differentiation during inflammation and reduced pathology in an experimental autoimmune encephalomyelitis model. These findings provide information about the molecular control of monocyte fate decision and identify ETV6 as a therapeutic target to redirect monocyte differentiation in inflammatory disorders.
Published: 2022

20. Contribution of endocrine therapy in oestrogen receptor-positive pT1a-b breast cancer: Results of a retrospective study

Author: Gilles Houvenaeghel, Alexandre de Nonneville, Monique Cohen, Jean-Marc Classe, Fabien Reyal, Chafika Mazouni, Christelle Faure, Alejandra Martinez, Marie-Pierre Chauvet, Emile Daraï, Charles Coutant, Pierre-Emmanuel Colombo, Pierre Gimbergues, Anne-Sophie Azuar, Roman Rouzier, Christine Tunon de Lara, Patrice Crochet, Sandrine Rua, Anthony Gonçalves, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Chirurgie Oncologique [Institut Paoli-Calmettes, Marseille], Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Département de chirurgie, Institut Curie [Paris], CRLCC Jean Godinot, Residual Tumor & Response to Treatment Laboratory [Paris] (RT2Lab), Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Institut du Cancer de Montpellier (ICM), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), Hopital de Grasse, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'oncologie chirurgicale, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Department of Obstetrics and Gynecology, Assistance Publique H^opitaux de Marseille, La Conception Hospital, 13005 Marseille, Aix Marseille University, France, and Aix Marseille Université (AMU)
Subjects: Cancer Research, Receptors, Estrogen, Oncology, Chemotherapy, Adjuvant, Receptor, ErbB-2, [SDV]Life Sciences [q-bio], Humans, Female, Breast Neoplasms, Disease-Free Survival, Retrospective Studies
Abstract: Introduction: Few data have been reported regarding endocrine therapy (ET) in patients with small pT1a-b ER-postive breast cancer (BC). Thus, we conducted a study to detect possible survival improvements due to ET in such patients. Methods: Our retrospective observational study included 5545 patients with pT1a-b ERpositive BC treated in 15 French centres, excluding patients with HER2-positive status, neoadjuvant chemotherapy, ER-negative status, unknown pN status or in situ BC. We estimated disease-free survival (DFS), recurrence-free survival (RFS) and overall survival (OS) via univariate analysis and multivariate Cox regression. Results: Most patients (80.3%: 4453) received ET and-when compared to those without ET -experienced increases of 2.5% and 3.3% in DFS and 1.9% and 4.3% in RFS after 5 and 7 years of follow-up, respectively, with little difference in OS. In Cox regression analysis, no ET was significantly associated with decreased DFS (hazard ratio, HR = 1.275, p = 0.047, 95% CI[1.003-1.620]) but not OS or RFS in all patients, while in 2363 patients with pT1ab ER-positive grade 2-3 BC, no ET was significantly associated with decreased DFS (HR = 1.502, p = 0.049, 95% CI[1.001-2.252]), but not OS (HR = 1.361, p = 0.272). ET omission was not significantly associated with decreased survival in 3047 patients with pT1a-b ER-positive grade 1 BC. Conclusion: Our results indicate that while ET provided a beneficial impact on survival to patients with pT1a-bN0 ER-positive BC-and especially in those with grade 2-3 tumours-no such impact was observed in grade 1 tumours. Consequently, ET should be discussed with these patients, particularly in those with pT1a grade 1 tumours. 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Published: 2022

21. Mutant Mice Lacking the p53 C-Terminal Domain Model Telomere Syndromes

Author: Sara Jaber, Ming Fang, Michel Huerre, Boris Bardot, Laure Charbonnier, Claire Soudais, Franck Toledo, Rachida Bouarich-Bourimi, Jean-Christophe Bourdon, Iva Simeonova, Irena Draskovic, Vincent Lejour, Arturo Londoño-Vallejo, Dynamique de l'information génétique : bases fondamentales et cancer (DIG CANCER), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), CD4+T-Lymphocytes and Anti-Tumour Response, University of Dundee, Département de Pathologie [Curie], Institut Curie [Paris], HAL UPMC, Gestionnaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Dynamique de l'information génétique : bases fondamentales et cancer ( DIG CANCER ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -INSTITUT CURIE-Centre National de la Recherche Scientifique ( CNRS ), Telomeres and Cancer Laboratory, INSTITUT CURIE, Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Curie, and Institut Curie
Subjects: Male, Telomere-Binding Proteins, Mutant, Gene Expression, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, TINF2, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, Dyskerin, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Mice, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Pulmonary fibrosis, medicine, Animals, Humans, Aplastic anemia, lcsh:QH301-705.5, 030304 developmental biology, 0303 health sciences, Mutation, Syndrome, Telomere, medicine.disease, Mice, Mutant Strains, Protein Structure, Tertiary, 3. Good health, Disease Models, Animal, lcsh:Biology (General), [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], 030220 oncology & carcinogenesis, Cancer research, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Tumor Suppressor Protein p53, Dyskeratosis congenita
Abstract: International audience; Mutations in p53, although frequent in human cancers , have not been implicated in telomere-related syndromes. Here, we show that homozygous mutant mice expressing p53 D31 , a p53 lacking the C-terminal domain, exhibit increased p53 activity and suffer from aplastic anemia and pulmonary fibrosis, hallmarks of syndromes caused by short telomeres. Indeed, p53 D31/D31 mice had short telomeres and other phenotypic traits associated with the telomere disease dyskeratosis congenita and its severe variant the Hoyeraal-Hreidarsson syndrome. Hetero-zygous p53 +/D31 mice were only mildly affected, but decreased levels of Mdm4, a negative regulator of p53, led to a dramatic aggravation of their symptoms. Importantly, several genes involved in telomere metabolism were downregulated in p53 D31/D31 cells, including Dyskerin, Rtel1, and Tinf2, which are mutated in dyskeratosis congenita, and Terf1, which is implicated in aplastic anemia. Together, these data reveal that a truncating mutation can activate p53 and that p53 plays a major role in the regulation of telomere metabolism.
Published: 2013
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22. Proportions of blood-borne Vd1þ and Vd2þ T-cells are associated with overall survival of melanoma patients treated with ipilimumab

Author: Kilian Wistuba-Hamprecht, Marnix H Geukes Foppen, Bastian Schilling, Karin Haehnel, Jedd D. Wolchok, Emanuela Romano, Elisabeth Steinhagen-Thiessen, Alexander Martens, Mariaelena Capone, Phillip Wong, Dirk Schadendorf, Jianda Yuan, Amir Khammari, Ilja Demuth, Brigitte Dréno, Claus Garbe, Graham Pawelec, Christian U. Blank, Michael A. Postow, Benjamin Weide, Paolo A. Ascierto, Anis Larbi, Department of Internal Medicine II, Eberhard Karls Universität Tübingen-Center for Medical Research, University of Tübingen, The Netherlands Cancer Institute, Memorial Sloan Kettering Cancer Center ( MSKCC ), Weill Medical College of Cornell University [New York], Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ), Service de dermatologie [Nantes], Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Istituto Nazionale Tumori IRCCS, Charité University Medical Center, Institute of Human Genetics, Singapore Immunology Network ( SIgN ), Agency for Science Technology and Research, German Cancer Consortium, Department of Dermatology, University Hospital Essen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen-Center for Medical Research, Memorial Sloane Kettering Cancer Center [New York], Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), and Bernardo, Elizabeth
Subjects: Oncology, Male, Cancer Research, Cellular differentiation, medicine.medical_treatment, Medizin, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, T-Lymphocyte Subsets, Medicine, Cytotoxic T cell, Melanoma, Aged, 80 and over, medicine.diagnostic_test, Antibodies, Monoclonal, Cell Differentiation, Receptors, Antigen, T-Cell, gamma-delta, Middle Aged, Flow Cytometry, Prognosis, 3. Good health, 030220 oncology & carcinogenesis, Biomarker (medicine), Female, Immunotherapy, medicine.drug, Adult, medicine.medical_specialty, Ipilimumab, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, Article, Flow cytometry, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Biomarkers, Tumor, Humans, Aged, business.industry, Case-control study, medicine.disease, Case-Control Studies, Immunology, business, 030215 immunology
Abstract: International audience; Human γδ T-cells possess regulatory and cytotoxic capabilities, and could potentially influence the efficacy of immunotherapies. We analysed the frequencies of peripheral γδ T-cells, including their most prominent subsets (Vδ1+ and Vδ2+ cells) and differentiation states in 109 melanoma patients and 109 healthy controls. We additionally analysed the impact of γδ T-cells on overall survival (OS) calculated from the first dose of ipilimumab in melanoma patients. Higher median frequencies of Vδ1+ cells and lower median frequencies of Vδ2+ cells were identified in patients compared to healthy subjects (Vδ1+: 30% versus 15%, Vδ2+: 39% versus 64%, both p < 0.001). Patients with higher frequencies of Vδ1+ cells (≥30%) had poorer OS (p = 0.043) and a Vδ1+ differentiation signature dominated by late-differentiated phenotypes. In contrast, higher frequencies of Vδ2+ cells (≥39%) were associated with longer survival (p = 0.031) independent of the M category or lactate dehydrogenase level. Patients with decreasing frequencies of Vδ2+ cells under ipilimumab treatment had worse OS and a lower rate of clinical benefit than patients without such decreases. Therefore, we suggest frequencies of both Vδ1+ and Vδ2+ cells as candidate biomarkers for outcome in melanoma patients following ipilimumab. Further studies are needed to validate these results and to clarify whether they represent prognostic associations or whether γδ T-cells are specifically and/or functionally linked to the mode of action of ipilimumab.
Published: 2016

23. Aryl Hydrocarbon Receptor Controls Monocyte Differentiation into Dendritic Cells versus Macrophages

Author: Elodie Segura, Paul Gueguen, Sylvain Baulande, Sebastian Amigorena, Alice Coillard, Tsing-Lee Tang-Huau, Christel Goudot, Adeline Cros, Nir Hacohen, Mylène Bohec, Siranush Sarkizova, Alexandra-Chloé Villani, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Department of Biomedical Informatics, Harvard Medical School [Boston] (HMS), Sanofi [Vitry-sur-Seine], SANOFI Recherche, Université Paris sciences et lettres (PSL), Institut Curie [Paris], Massachusetts General Hospital [Boston], Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Broad Institute of MIT and Harvard ( BROAD INSTITUTE ), Harvard Medical School [Boston] ( HMS ) -Massachusetts General Hospital [Boston] ( MGH ) -Massachusetts Institute of Technology ( MIT ), Harvard Medical School [Boston] ( HMS ), PSL Research University ( PSL ), Institut Curie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5), and PSL Research University (PSL)
Subjects: 0301 basic medicine, Male, [ SDV.IMM.IA ] Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Monocytes, Mice, 0302 clinical medicine, Neoplasms, Immunology and Allergy, Cluster Analysis, Cells, Cultured, Mice, Knockout, biology, Ascites, 3. Good health, Cell biology, Infectious Diseases, medicine.anatomical_structure, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, MAFB, 030220 oncology & carcinogenesis, Monocyte differentiation, Interferon Regulatory Factors, Cytokines, Female, Immunology, MafB Transcription Factor, 03 medical and health sciences, In vivo, Leprosy, medicine, Animals, Humans, Transcription factor, [ SDV.IMM.II ] Life Sciences [q-bio]/Immunology/Innate immunity, Monocyte, Gene Expression Profiling, Macrophages, Dendritic Cells, Aryl hydrocarbon receptor, In vitro, Repressor Proteins, 030104 developmental biology, Gene Expression Regulation, Receptors, Aryl Hydrocarbon, biology.protein, Positive Regulatory Domain I-Binding Factor 1, Transcriptome, IRF4
Abstract: International audience; After entering tissues, monocytes differentiate into cells that share functional features with either macrophages or dendritic cells (DCs). How monocyte fate is directed toward monocyte-derived macrophages (mo-Macs) or monocyte-derived DCs (mo-DCs) and which transcription factors control these differentiation pathways remains unknown. Using an in vitro culture model yielding human mo-DCs and mo-Macs closely resembling those found in vivo in ascites, we show that IRF4 and MAFB were critical regulators of monocyte differentiation into mo-DCs and mo-Macs, respectively. Activation of the aryl hydrocarbon receptor (AHR) promoted mo-DC differentiation through the induction of BLIMP-1, while impairing differentiation into mo-Macs. AhR deficiency also impaired the in vivo differentiation of mouse mo-DCs. Finally, AHR activation correlated with mo-DC infiltration in leprosy lesions. These results establish that mo-DCs and mo-Macs are controlled by distinct transcription factors and show that AHR acts as a molecular switch for monocyte fate specification in response to micro-environmental factors.
Published: 2016

24. Effective antitumor therapy based on a novel antibody-drug conjugate targeting the Tn carbohydrate antigen

Author: Frédéric Schmidt, Xavier Sastre-Garau, Cornélie Batisse, Sebastian Amigorena, Rafik Ait Sarkouh, Pascale Hubert, Eliane Piaggio, Eduardo Osinaga, Philippe De La Rochere, Nathalie Amzallag, Pablo Oppezzo, Christine Sedlik, Adele Heitzmann, Otto Pritsch, Sophie Viel, Chimie biologique des membranes et ciblage thérapeutique (CBMCT - UMR 3666 / U1143), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique Biothérapie (CICBT), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Facultad de Medicina [Montevideo], Universidad de la República [Montevideo] (UDELAR), Institut Pasteur de Montevideo, Réseau International des Instituts Pasteur (RIIP), Biologie des Tumeurs, Institut Curie [Paris], This work was supported by fundings from the Institut National de la Santé et de la Recherche Médicale (INSERM), the Association pour la Recherche sur le Cancer (ARC), the Institut Curie, the Agence Nationale pour la Recherche (ANR Emergence program), and the Institut National du Cancer (INCa)., SCHMIDT, Frédéric, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre d'Investigation Clinique Biothérapie ( CICBT ), Chimie biologique des membranes et ciblage thérapeutique ( CBMCT - UMR 3666 / U1143 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Universidad de la República, Réseau International des Instituts Pasteur ( RIIP ) -Institut Pasteur de Montevideo, and INSTITUT CURIE
Subjects: 0301 basic medicine, Antibody-drug conjugate, Saporin, medicine.drug_class, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Immunology, Tn antigen, Monoclonal antibody, 03 medical and health sciences, 0302 clinical medicine, Biodistribution, Antigen, In vivo, [CHIM] Chemical Sciences, medicine, Immunology and Allergy, [CHIM]Chemical Sciences, Cytotoxicity, monoclonal antibody-drug conjugate, ComputingMilieux_MISCELLANEOUS, Original Research, [ SDV ] Life Sciences [q-bio], biology, Immunotherapy, Molecular biology, 3. Good health, [SDV] Life Sciences [q-bio], internalization, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Cancer research, biology.protein, MMAF
Abstract: International audience; Antibody-drug conjugates (ADC), combining the specificity of tumor recognition by monoclonal antibodies (mAb) and the powerful cytotoxicity of anticancer drugs, are currently under growing interest and development. Here, we studied the potential of Chi-Tn, a mAb directed to a glyco-peptidic tumor-associated antigen, to be used as an ADC for cancer treatment. First, we demonstrated that Chi-Tn specifically targeted tumor cells in vivo. Also, using flow cytometry and deconvolution microscopy, we showed that the Chi-Tn mAb is rapidly internalized - condition necessary to ensure the delivery of conjugated cytotoxic drugs in an active form, and targeted to early and recycling endosomes. When conjugated to saporin (SAP) or to auristatin F, the Chi-Tn ADC exhibited effective cytotoxicity to Tn-positive tumor cells in vitro, which correlated with the level of tumoral Tn expression. Furthermore, the Chi-Tn mAb conjugated to auristatin F also exhibited efficient antitumor activity in vivo, validating for the first time the use of an anti-Tn antibody as an effective ADC.
Published: 2016

25. Baseline Peripheral Blood Biomarkers Associated with Clinical Outcome of Advanced Melanoma Patients Treated with Ipilimumab

Author: Phillip Wong, Dirk Schadendorf, Christian U. Blank, Antje Sucker, Bastian Schilling, Thomas Eigentler, Jianda Yuan, Emanuela Romano, Alexander Martens, Marnix H Geukes Foppen, Kilian Wistuba-Hamprecht, Mariaelena Capone, Jedd D. Wolchok, Graham Pawelec, Brigitte Dréno, Claus Garbe, Amir Khammari, Peter Martus, Anna Maria Di Giacomo, Jessica C. Hassel, Michael A. Postow, Paolo A. Ascierto, Benjamin Weide, Michele Maio, Department of Internal Medicine II, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen-Center for Medical Research, University of Tübingen, Department of Dermatology [Tubingen, Germany], Tübingen University Hospital [Germany], The Netherlands Cancer Institute, Memorial Sloane Kettering Cancer Center [New York], Weill Medical College of Cornell University [New York], Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de dermatologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Dermatology, University Hospital Essen, Fondazione IRCCS Istituto Nazionale dei Tumori, Division of Medical Oncology and Immunotherapy, University Hospital of Siena, German Cancer Consortium, Heidelberg University Hospital [Heidelberg], Department of Immunology [Tübingen, Germany], Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Bernardo, Elizabeth, University of Tübingen [Germany], Eberhard Karls Universität Tübingen-Center for Medical Research, Memorial Sloan Kettering Cancer Center ( MSKCC ), Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), and CHU Angers-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes )
Subjects: Male, Oncology, Cancer Research, medicine.medical_specialty, Skin Neoplasms, Lymphocyte, Medizin, Ipilimumab, [SDV.CAN]Life Sciences [q-bio]/Cancer, T-Lymphocytes, Regulatory, Article, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Antineoplastic Agents, Immunological, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Biomarkers, Tumor, medicine, Humans, Lymphocyte Count, IL-2 receptor, Adverse effect, Melanoma, Aged, L-Lactate Dehydrogenase, Proportional hazards model, business.industry, Myeloid-Derived Suppressor Cells, FOXP3, Cancer, medicine.disease, 3. Good health, Treatment Outcome, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, Erythrocyte Count, Biomarker (medicine), Female, business, 030215 immunology, medicine.drug
Abstract: Purpose: To identify baseline peripheral blood biomarkers associated with clinical outcome following ipilimumab treatment in advanced melanoma patients. Experimental Design: Frequencies of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg), serum lactate dehydrogenase (LDH), routine blood counts, and clinical characteristics were assessed in 209 patients. Endpoints were overall survival (OS) and best overall response. Statistical calculations were done by Kaplan–Meier and Cox regression analysis, including calibration and discrimination by C-statistics. Results: Low baseline LDH, absolute monocyte counts (AMC), Lin−CD14+HLA-DR−/low-MDSC frequencies, and high absolute eosinophil counts (AEC), relative lymphocyte counts (RLC), and CD4+CD25+FoxP3+-Treg frequencies were significantly associated with better survival, and were considered in a combination model. Patients (43.5%) presenting with the best biomarker signature had a 30% response rate and median survival of 16 months. In contrast, patients with the worst biomarkers (27.5%) had only a 3% response rate and median survival of 4 months. The occurrence of adverse events correlated with neither baseline biomarker signatures nor the clinical benefit of ipilimumab. In another model, limited to the routine parameters LDH, AMC, AEC, and RLC, the number of favorable factors (4 vs. 3 vs. 2–0) was also associated with OS (P < 0.001 for all pairwise comparisons) in the main study and additionally in an independent validation cohort. Conclusions: A baseline signature of low LDH, AMC, and MDSCs as well as high AEC, Tregs, and RLC is associated with favorable outcome following ipilimumab. Prospective investigation of the predictive impact of these markers following ipilimumab and other treatments, e.g., PD-1 antibodies, is warranted. Clin Cancer Res; 22(12); 2908–18. ©2016 AACR.
Published: 2016

26. Indium Tin Oxide Microsystem for Electrochemical Detection of Exocytosis of Migratory Dendritic Cells

Author: Marine Bretou, Ana-Maria Lennon-Duménil, Frédéric Lemaître, Xiaoqing Liu, Manon Guille-Collignon, Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Université Pierre et Marie Curie - Paris 6 (UPMC), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure - Paris (ENS-PSL), École normale supérieure - Paris ( ENS Paris ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Curie, and HAL-UPMC, Gestionnaire
Subjects: 0301 basic medicine, [SPI.NANO] Engineering Sciences [physics]/Micro and nanotechnologies/Microelectronics, Nanotechnology, 01 natural sciences, Dendritic cells, Exocytosis, Analytical Chemistry, 03 medical and health sciences, chemistry.chemical_compound, [ CHIM.OTHE ] Chemical Sciences/Other, Electrochemistry, Extracellular, Electrochemical detection, Cell migration, Endocytotic Process, [SPI.NANO]Engineering Sciences [physics]/Micro and nanotechnologies/Microelectronics, Polydimethylsiloxane, 010405 organic chemistry, Pinocytosis, technology, industry, and agriculture, 0104 chemical sciences, Indium tin oxide, 030104 developmental biology, Membrane, chemistry, [CHIM.OTHE] Chemical Sciences/Other, Biophysics, [ SPI.NANO ] Engineering Sciences [physics]/Micro and nanotechnologies/Microelectronics, ITO microsystem, [CHIM.OTHE]Chemical Sciences/Other
Abstract: International audience; The design, fabrication and test of an indium tin oxide (ITO) microdevice to investigate exocytotic behaviors of migratory dendritic cells (DCs) in confined three-dimensional environment were reported in this work. Indeed, immature DCs were able to migrate into micro-fabricated biocompatible polydimethylsiloxane (PDMS) channels that mimic their natural constrained environment of tissues for patrolling in search of danger associated antigens through an endocytotic process called macropinocytosis. In order to coordinate membrane trafficking and prevent cell volume increment, DCs will release part of their contents back to the extracellular medium while migrating. Through electrochemical measurements, we demonstrated that exocytotic events of migratory DCs could be monitored by our ITO microdevice. In addition, the transparency of ITO electrode should facilitate future combining assays of exocytosis with other fluorescence-based measurements of cell physiology.
Published: 2016

27. Renal replacement therapy in adult and pediatric intensive care: Recommendations by an expert panel from the French Intensive Care Society (SRLF) with the French Society of Anesthesia Intensive Care (SFAR) French Group for Pediatric Intensive Care Emergencies (GFRUP) the French Dialysis Society (SFD)

Author: Emma Allain-Launay, Lionel Velly, Damien Ducheyron, David Osman, Patrick Vaillant, Christophe Ridel, Annie Lahoche, Etienne Javouhey, Michael Darmon, Christophe Vinsonneau, Ly Van Phach Vong, Matthieu Legrand, Clarisse Blayau, Serge Letacon, T. Gaillot, Patrick M. Honore, René Robert, Frédérique Schortgen, Thierry Krummel, Bertrand Souweine, Mehran Monchi, Centre hospitalier Marc Jacquet (Melun), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Pontchaillou [Rennes], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Unité Mixte de Recherche Epidémiologique et de Surveillance Transport Travail Environnement (UMRESTTE UMR T9405), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR), Biomarqueurs CArdioNeuroVASCulaires (BioCANVAS), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Laboratoire Microorganismes : Génome et Environnement (LMGE), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Centre National de la Recherche Scientifique (CNRS), CHU Marseille, Inserm U925, équipe avenir, Développement normal et pathologique des lymphocytes et signalisation, Université de Picardie Jules Verne (UPJV)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Picardie Jules Verne (UPJV)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers, INSERM U955, équipe 13, Service d'anesthésie-réanimation SAMU94-SMUR94 [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Université d'Auvergne - Clermont-Ferrand I (UdA), Supporting clinical sciences, Internal Medicine Specializations, Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ), Biomarqueurs CArdioNeuroVASCulaires ( BioCANVAS ), Université Paris 13 ( UP13 ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Picardie Jules Verne ( UPJV ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Picardie Jules Verne ( UPJV ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT ), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10, Laboratoire Microorganismes : Génome et Environnement ( LMGE ), and Université Blaise Pascal - Clermont-Ferrand 2 ( UBP ) -Université d'Auvergne - Clermont-Ferrand I ( UdA ) -Centre National de la Recherche Scientifique ( CNRS )
Subjects: medicine.medical_specialty, Continuous renal replacement therapy, Kidney Disease, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Clinical Sciences, 030232 urology & nephrology, Renal and urogenital, Review, 030204 cardiovascular system & hematology, Recommendations, Critical Care and Intensive Care Medicine, urologic and male genital diseases, Peritoneal dialysis, 03 medical and health sciences, Anticoagulation, 0302 clinical medicine, Intensive care, Anesthesiology, medicine, Renal replacement therapy, Intensive care medicine, Dialysis, Medicine(all), [ SDV ] Life Sciences [q-bio], business.industry, Dialysis dose, Dialysis catheter, 3. Good health, Renal Replacement Therapy, Catheter, Anesthesia, Hemodialysis, Emergency medicine, recommendations, Public Health and Health Services, business, Citrate
Abstract: International audience; Acute renal failure (ARF) in critically ill patients is currently very frequent and requires renal replacement therapy (RRT) in many patients. During the last 15 years, several studies have considered important issues regarding the use of RRT in ARF, like the time to initiate the therapy, the dialysis dose, the types of catheter, the choice of technique, and anticoagulation. However, despite an abundant literature, conflicting results do not provide evidence on RRT implementation. We present herein recommendations for the use of RRT in adult and pediatric intensive care developed with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system by an expert group of French Intensive Care Society (SRLF), with the participation of the French Society of Anesthesia and Intensive Care (SFAR), the French Group for Pediatric Intensive Care and Emergencies (GFRUP), and the French Dialysis Society (SFD). The recommendations cover 4 fields: criteria for RRT initiation, technical aspects (access routes, membranes, anticoagulation, reverse osmosis water), practical aspects (choice of the method, peritoneal dialysis, dialysis dose, adjustments), and safety (procedures and training, dialysis catheter management, extracorporeal circuit set-up). These recommendations have been designed on a practical point of view to provide guidance for intensivists in their daily practice
Published: 2015

28. Changes in gene expression control by DNA methylation in cancer

Author: Moarii, Matahi, Boeva, Valentina, Vert, Jean-Philippe, Reyal, Fabien, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Bioinformatique (CBIO), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Institut Curie [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Transfert, Institut Curie, Department of Surgery, Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), MINES ParisTech - École nationale supérieure des mines de Paris-PSL Research University (PSL), Institut Curie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5), MINES ParisTech - École nationale supérieure des mines de Paris-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -INSTITUT CURIE, Centre de Bioinformatique ( CBIO ), MINES ParisTech - École nationale supérieure des mines de Paris-PSL Research University ( PSL ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), and INSTITUT CURIE
Subjects: [ SDV.BIBS ] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2015

29. Biologie des cellules MAIT chez la souris

Author: Cui, Yue, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Sorbonne Paris Cité, Olivier Lantz, Immunité et cancer ( U932 ), and Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: Les cellules MAIT, Les souris sauvages, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, RORγt, Wild-derived inbred mice, MAIT cell
Abstract: Mucosal-associated invariant T cells (MAIT) are innate lymphocytes that express a semi-invariant T cell receptor (iTCR) and are restricted by the major histocompatibility complex (MHC) related molecule, MR1. In human, MAIT cells are abundant in the blood (1-10%), gut (3-5%), and liver (20-40%). They react against microbial-derived riboflavin metabolites that are common in bacteria and yeast. Due to the paucity of MAIT cells in classical inbred laboratory mice, studies on mouse MAIT cells were mostly performed in TCR-transgenic (Tg) mice. However, these Tg MAIT cells do not adequately recapitulate the phenotype of human MAIT cells. Herein, we present a recently generated congenic mouse strain harboring MAIT cells that closely resemble human MAIT cells and use this tool to study the characteristics of natural mouse MAIT cell. An analysis of wild-derived inbred mouse strains revealed that CAST/Ei strain has increased frequency of MAIT cells than C57BL/6 mice. This was linked to a locus on the TCRα region. Introduction of such locus into C57BL/6 mice generated a “MAIT” congenic strain, which were further crossed to Rorc(γt)-GfpTG reporter strain based on previous findings of RORγt expression on human MAIT cells. Using this tool, we show that natural mouse MAIT cells are CD4−CD8−/lo, display an effector memory phenotype (CD44+), and coexpress the transcription factors PLZF and RORγt. They exhibit tissue-homing properties (CCR6+CCR7−) and preferentially reside in peripheral non-lymphoid tissues, including lung, liver, and skin. Upon TCR ligation, MAIT cells produce TH1/2/17 type cytokines and react to bacterial-derived antigens (i.e. semi-purified bacterial fraction or 5-OP-RU) in an MR1-dependent manner. They have high expression of cytokine receptors (IL-7R, IL-18Rα, IL-12Rβ) and may respond to the corresponding innate cytokines. During experimental urinary tract infection, MAIT cells migrate to the bladder and display a protective anti-bacterial activity. Altogether, our results demonstrate that mouse MAIT cells resemble their human counterparts more closely than previously recognized and therefore this new mouse model will be a powerful tool for advancing our understanding of MAIT cell biology in health and disease.; Les cellules T invariantes associées aux muqueuse (MAIT) sont des lymphocytes innés caractérisés par l'expression d'un récepteur des cellules T semi-invariant (iTCR) et restreints par la molécule du complexe majeur d'histocompatibilité de classe Ib, MR1. Chez l'homme, les cellules MAIT sont abondantes dans le sang (1 à 10%), l'intestin (3 à 5%) et le foie (20 à 40%) et réagissent contre des métabolites microbiens. En raison de leur rareté dans les souris de laboratoire classiques, les études sur les cellules MAIT murines ont été principalement effectuées sur des souris transgéniques (Tg) pour des TCR MAIT. Cependant, ces cellules MAIT Tg ne récapitulent pas de manière adéquate le phénotype des cellules MAIT humaines. Ici, nous décrivons une souche de souris congénique que nous avons générée qui possède des cellules MAIT qui ressemblent aux cellules MAIT humaines. Nous utilisons cet outil pour étudier les caractéristiques des cellules MAIT murines. L'étude de souches de souris consanguines d'origine sauvage montre que la souche CAST/Ei présente une fréquence des cellules MAIT nettement supérieur à celle retrouvée dans la souche C57BL/6. Un seul locus est impliqué et a été localisé dans la région TCRα. Ceci a permis la génération d'une souche "MAIT" congénique, qui ont été en outre croisé à une souris Tg pour un rapporteur GFP du facteur transcriptionnel RORγt sur la base de données antérieurs montrant que les MAITs humaines expriment ce facteur. Grâce à cet outil, nous montrons que les MAITs murines sont CD4−CD8−/lo, ont un phénotype mémoire effecteurs (CD44+) et coexpriment PLZF et RORγt. Ces MAITs murines sont orientées vers une localisation tissulaire (CCR6+CCR7−) et résident préférentiellement dans les tissus non lymphoïdes périphériques, y compris les poumons, le foie et la peau. Après stimulation du TCR, les MAITs produisent des cytokines TH1/2/17 et sont aussi activées par de antigènes bactériens (par exemple semi-purifié fraction bactérienne ou 5-OP-RU) d'une manière dépendant de MR1. Les MAITs ont une forte expression de récepteurs de cytokines (IL-7R, IL-18Rα, IL-12Rβ) et peuvent ainsi répondre à des cytokines innées. Lors d'une infection expérimentale des voies urinaires, les MAITs migrent vers la vessie et ont une activité protectrice anti-bactérienne. Au total, nos résultats démontrent que les cellules MAIT murines ressemblent étroitement à leurs homologues humains. Ce nouveau modèle murin sera un outil puissant pour faire avancer notre compréhension de la biologie des cellules MAIT en situation normale et pathologique.
Published: 2015

30. Integrative DNA methylation and gene expression analysis to assess the universality of the CpG island methylator phenotype

Author: Matahi Moarii, Jean-Philippe Vert, Fabien Reyal, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Bioinformatique (CBIO), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Institut Curie [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Transfert, Institut Curie, Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -INSTITUT CURIE, Centre de Bioinformatique ( CBIO ), MINES ParisTech - École nationale supérieure des mines de Paris-PSL Research University ( PSL ), Institut Curie, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), INSTITUT CURIE, MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), MINES ParisTech - École nationale supérieure des mines de Paris-PSL Research University (PSL), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5)
Subjects: Biology, Neoplasms, Drug Discovery, Databases, Genetic, Genetics, medicine, Biomarkers, Tumor, Humans, Epigenetics, Neoplasm Metastasis, [ SDV.BIBS ] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Molecular Biology, neoplasms, ComputingMilieux_MISCELLANEOUS, Regulation of gene expression, CpG Island Methylator Phenotype, Genome, Human, Cancer, DNA Methylation, medicine.disease, Prognosis, Phenotype, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Human genetics, digestive system diseases, 3. Good health, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, CpG site, DNA methylation, Mutation, Cancer research, Molecular Medicine, CpG Islands, Primary Research
Abstract: Background The CpG island methylator phenotype (CIMP) was first characterized in colorectal cancer but since has been extensively studied in several other tumor types such as breast, bladder, lung, and gastric. CIMP is of clinical importance as it has been reported to be associated with prognosis or response to treatment. However, the identification of a universal molecular basis to define CIMP across tumors has remained elusive. Results We perform a genome-wide methylation analysis of over 2000 tumor samples from 5 cancer sites to assess the existence of a CIMP with common molecular basis across cancers. We then show that the CIMP phenotype is associated with specific gene expression variations. However, we do not find a common genetic signature in all tissues associated with CIMP. Conclusion Our results suggest the existence of a universal epigenetic and transcriptomic signature that defines the CIMP across several tumor types but does not indicate the existence of a common genetic signature of CIMP. Electronic supplementary material The online version of this article (doi:10.1186/s40246-015-0048-9) contains supplementary material, which is available to authorized users.
Published: 2015

31. Intensive chemotherapy followed by autologous stem cell transplantation in primary central nervous system lymphomas (PCNSLs). Therapeutic outcomes in real life—experience of the French Network

Author: Schenone, Laurence, Houillier, Caroline, Tanguy, Marie Laure, Choquet, Sylvain, Agbetiafa, Kossi, Ghesquières, Hervé, Damaj, Gandhi, Schmitt, Anna, Bouabdallah, Krimo, Ahle, Guido, Gressin, Remy, Cornillon, Jérôme, Houot, Roch, Marolleau, Jean-Pierre, Fornecker, Luc-Matthieu, Chinot, Olivier, Peyrade, Frédéric, Bouabdallah, Reda, Moluçon-Chabrot, Cécile, Gyan, Emmanuel, Chauchet, Adrien, Casasnovas, Olivier, Oberic, Lucie, Delwail, Vincent, Abraham, Julie, Roland, Virginie, Waultier-Rascalou, Agathe, Willems, Lise, Morschhauser, Franck, Fabbro, Michel, Ursu, Renata, Thieblemont, Catherine, Jardin, Fabrice, Tempescul, Adrian, Malaise, Denis, Touitou, Valérie, Nichelli, Lucia, Le Garff-Tavernier, Magali, Plessier, Aurélie, Bourget, Philippe, Bonmati, Caroline, Wantz-Mézières, Sophie, Giordan, Quentin, Dorvaux, Véronique, Charron, Cyril, Jabeur, Waliyde, Hoang-Xuan, Khê, Taillandier, Luc, Soussain, Carole, Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département d'hématologie, Institut Curie, Site Saint-Cloud, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Institut Bergonié [Bordeaux], UNICANCER, CHU Bordeaux [Bordeaux], Service de Neurologie [Hôpitaux Civils de Colmar], Hôpitaux Civils Colmar, Centre Hospitalier Universitaire [Grenoble] (CHU), Institut de Cancérologie Lucien Neuwirth, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Amiens-Picardie, HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Strasbourg, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d’Hématologie Biologique [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Dupuytren [CHU Limoges], Centre Hospitalier Saint Jean de Perpignan, Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut du Cancer de Montpellier (ICM), Hopital Saint-Louis [AP-HP] (AP-HP), NF-kappaB, Différenciation et Cancer (OncokappaB (URP_7324)), Université Paris Cité (UPCité), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Département d'Oncologie Chirurgicale [Institut Curie], Institut Curie [Paris], Laboratoire d'Imagerie Translationnelle en Oncologie (LITO ), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Beaujon [AP-HP], CHU Necker - Enfants Malades [AP-HP], Biology, genetics and statistics (BIGS), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut Élie Cartan de Lorraine (IECL), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut Élie Cartan de Lorraine (IECL), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Hôpital de Mercy, Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), Hôpital Ambroise Paré [AP-HP], Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre de Recherche en Automatique de Nancy (CRAN), Institut Curie - Saint Cloud (ICSC), Immunité et cancer (U932), and We thank the clinicians involved in the French National 'Lymphome Oculo-Cérébral' LOC network, part of the network for rare cancers of the central nervous system, 'RENOCLIP-LOC Network', approved by the French National Institute of Cancer (INCa).
Subjects: Transplantation, Hematology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; We analysed the therapeutic outcomes of all consecutive patients with primary central nervous system lymphoma (PCNSL) registered in the prospective French database for PCNSL and treated with intensive chemotherapy (IC) followed by autologous stem cell transplantation (IC-ASCT) between 2011 and November 2019 (271 patients recruited, 266 analysed). In addition, treatment-related complications of thiotepa-based IC-ASCT were analysed from the source files of 85 patients from 3 centers. Patients had received IC-ASCT either in first-line treatment (n\,=\,147) or at relapse (n\,=\,119). The median age at IC-ASCT was 57 years (range: 22-74). IC consisted of thiotepa-BCNU (n\,=\,64), thiotepa-busulfan (n\,=\,24), BCNU-etoposide-cytarabine-melphalan (BEAM, n\,=\,36) and thiotepa-busulfan-cyclophosphamide (n\,=\,142). In multivariate analysis, BEAM and ASCT beyond the first relapse were adverse prognostic factors for relapse risk. The risk of treatment-related mortality was higher for ASCT performed beyond the first relapse and seemed higher for thiotepa-busulfan-cyclophosphamide. Thiotepa-BCNU tends to result in a higher relapse rate than thiotepa-busulfan-cyclophosphamide and thiotepa-busulfan. This study confirms the role of IC-ASCT in first-line treatment and at first-relapse PCNSL (5-year overall survival rates of 80 and 50%, respectively). The benefit/risk ratio of thiotepa-busulfan/thiotepa-busulfan-cyclophosphamide-ASCT could be improved by considering ASCT earlier in the course of the disease and dose adjustment of the IC.
Published: 2022

32. Real-Time Detection of ESR1 Mutation in Blood by Droplet Digital PCR in the PADA-1 Trial: Feasibility and Cross-Validation with NGS

Author: Celine Callens, Francois-Clement Bidard, Anaïs Curto-Taribo, Olfa Trabelsi-Grati, Samia Melaabi, Suzette Delaloge, Anne-Claire Hardy-Bessard, Thomas Bachelot, Florian Clatot, Thibault De La Motte Rouge, Jean-Luc Canon, Laurent Arnould, Fabrice Andre, Sandrine Marques, Marc-Henri Stern, Jean-Yves Pierga, Anne Vincent-Salomon, Camille Benoist, Emmanuelle Jeannot, Frederique Berger, Ivan Bieche, Anne Pradines, Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Centre Armoricain de Radiothérapie, d'Imagerie médicale et d'Oncologie [Plérin, Saint-Brieuc] (CARIO), Centre Léon Bérard [Lyon], Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Centre Eugène Marquis (CRLCC), Département de Biologie et pathologie des tumeurs [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, UNICANCER, Unité de génétique et biologie des cancers (U830), Université Paris Cité - UFR Médecine Paris Centre [Santé] (UPC Médecine Paris Centre), Université Paris Cité (UPC), Institut Curie [Paris], Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Claudius Regaud, Pfizer, AstraZeneca, Roche, Ministère des Affaires Sociales et de la Santé, Institut National Du Cancer, INCa: PRT-K19-110, Institut Curie: INCa-DGOS-INSERM_12554, The authors declare the following competing financial interest(s): F.-C.B.: Grants from Pfizer during the conduct of the study, grants, personal fees, and nonfinancial support from Pfizer and Novartis personal fees from Lilly, Amgen, Sanofi, and Radius personal fees and nonfinancial support from Roche and AstraZeneca, grants and personal fees from Seagen, and grants from Prolynx outside the submitted work, and a pending patent on ctDNA detection by ddPCR. F.-C.B., M.-H.S., and E.J. are coholders of a patent related to ESR1 mutation detection (PCT/EP2019/056445). S.D.: Consulting Fees (e.g., advisory boards), Author, AstraZeneca, Besins, Rappta. Contracted Research, Pfizer, MSD, BMS, AstraZeneca, Orion, Sanofi, Novartis, Puma, Roche, Lilly, Daich. A.-C.H.-B.: Personal fees from AstraZeneca, Daiichi, Clovis, GSK, MSD, Novartis, Pfizer, and Roche outside the submitted work. T.B.: Consulting Fees (e.g., advisory boards), AstraZeneca, SeaGen, Roche, Novartis, Pfizer. Contracted Research, Roche, AstraZeneca, Pfizer, SeaGen. T.D.L.M.R.: Consulting Fees (e.g., advisory boards), AstraZeneca, Clovis Oncology, Eisai, MSD, Novartis, Pfizer, Roche, Sanofi, Tesaro. Contracted Research, Novartis, Pfizer, AstraZeneca. Other, AstraZeneca, MSD, Roche, Pfizer. F.A.: Grants from Roche, AstraZeneca, Daiichi Sankyo, Pfizer, Novartis, and Lilly outside the submitted work. M.S.: Receipt of Intellectual Property Rights/Patent Holder, patent on ESR1 ddPCR. J.P.: Consulting Fees (e.g., advisory boards), Exact Sciences, AstraZeneca, Daiichi, Sankyo, Lilly, Novartis, Pfizer, Pierre Fabre, Oncology, Roche, SeaGen. Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speaker bureaus), Amgen, MSD, Novartis, Pfizer, SeaGen. Contracted Research, Servier, Roche. F.J.: Receipt of Intellectual Property Rights/Patent Holder, patent on ESR1 ddPCR. Acknowledgments, and This study was supported by a grant from the French Ministry of Health and the French National Cancer Institute (Grant PRT-K19-110) and Pfizer. The PADA-1 trial was funded by Pfizer through a grant to Unicancer. The initial development of the bESR1 assay used in the trial was supported by the Institut Curie SIRIC2 program (Grant INCa-DGOS-INSERM_12554). mut
Subjects: [CHIM.ANAL]Chemical Sciences/Analytical chemistry, Mutation, Feasibility Studies, High-Throughput Nucleotide Sequencing, Humans, Polymerase Chain Reaction, Circulating Tumor DNA, Analytical Chemistry
Abstract: International audience; The clinical actionability of circulating tumor DNA requires sensitive detection methods with a short turnaround time. In the PADA-1 phase 3 trial (NCT03079011), metastatic breast cancer patients treated with an aromatase inhibitor and palbociclib were screened every 2 months for activating ESR1 mutations in blood (bESR1mut). We report the feasibility of the droplet digital polymerase chain reaction (ddPCR) and cross-validation with next-generation sequencing (NGS). bESR1mut testing was centralized in two platforms using the same ddPCR assay. Results were reported as copies/mL of plasma and mutant allele frequency (MAF). We analyzed 200 positive ddPCR samples with an NGS assay (0.5-1% sensitivity). Overall, 12,552 blood samples were collected from 1017 patients from 83 centers. Among the 12,525 available samples with ddPCR results, 11,533 (92%) were bESR1mut-negative. A total of 267 patients newly displayed bESR1mut (26% patients/2% samples) with a median copy number of 14/mL (range: 4-1225) and a median MAF of 0.83% (0.11-35), 648 samples (20% patients/5% samples) displayed persistent bESR1mut, and 77 (
Published: 2022

33. The L1 major capsid protein of HPV16 differentially modulates APC trafficking according to the vaccination or natural infection context

Author: Pascale Hubert, Philippe Delvenne, Latifa Bousarghin, Yves Henrotin, Michael Herfs, Ludivine Herman, Jacques Boniver, Gaelle Kustermans, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Bone and Cartilage Research Unit, Université de Liège, Microbiologie : Risques Infectieux, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-Faculté de Chirurgie Dentaire de Rennes-Faculté d'Odontologie-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Experimental Pathology, GIGA-Research, Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Curie, Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -CHU Pontchaillou [Rennes]-Faculté de Chirurgie Dentaire de Rennes-Faculté d'Odontologie-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes - UFR d'Odontologie (UR Odontologie), Université de Rennes (UR)-Université de Rennes (UR), and Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Keratinocytes, Receptors, CXCR4, Chemokine, viruses, Immunology, Motility, Context (language use), Biology, Dinoprostone, 03 medical and health sciences, 0302 clinical medicine, Immune system, [ SDV.MP ] Life Sciences [q-bio]/Microbiology and Parasitology, Cell Movement, medicine, Immunology and Allergy, Papillomavirus Vaccines, Receptor, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Human papillomavirus 16, 0303 health sciences, Papillomavirus Infections, virus diseases, Oncogene Proteins, Viral, Epithelium, 3. Good health, Cell biology, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, medicine.anatomical_structure, Gene Expression Regulation, Langerhans Cells, 030220 oncology & carcinogenesis, biology.protein, Capsid Proteins, Lymph Nodes, Signal transduction, Keratinocyte
Abstract: Human papillomavirus (HPV) infection, particularly type 16, is causally associated with cancer of the uterine cervix. The progression of cervical lesions suggests that viral antigens are not adequately presented to the immune system. The aim of this study was to determine whether HPV16 viral particles can influence the trafficking of human DC/Langerhans cells (LC), either by direct interactions with DC or following incubation with human normal keratinocytes that are in close contact with LC in the squamous epithelium. We first demonstrated that HPV16 L1 major capsid protein, when self-assembled into virus-like particles (VLP), is able to induce in DC an over-expression of CXC receptor 4 (CXCR4) via the activation of the NF-κB signaling pathway and to enhance DC motility in the presence of CXCL12, suggesting an ability to migrate towards lymph nodes. We also showed that conditioned media of HPV16 VLP-treated keratinocytes induce a lower LC migration than those from untreated keratinocytes and that prostaglandin E2 (PGE(2)), detected in HPV16 VLP-treated keratinocyte supernatants, may reduce LC recruitment into the squamous epithelium. Taken together, our data demonstrate that HPV16 VLP may differentially regulate the immune protective response according to their target cells.
Published: 2010

34. Guidelines for the use of flow cytometry and cell sorting in immunological studies

Author: Guadalupe Herrera, Jens Geginat, Daryl Grummitt, Vincenzo Barnaba, Joanne Lannigan, Beate Rückert, Elisabetta Traggiai, Christian Münz, Susanne Melzer, Ari Waisman, Pratip K. Chattopadhyay, Jonas Hahn, T. Vincent Shankey, S Schmid, Julia Tornack, David W. Hedley, Paolo Dellabona, Jürgen Wienands, Ana Cumano, Ester B. M. Remmerswaal, Christopher A. Hunter, Van Duc Dang, Anis Larbi, Timothy P. Bushnell, Mor Gross, Wenjun Ouyang, Vera S. Donnenberg, Lilly Lopez, Holden T. Maecker, Jenny Mjösberg, Christina Stehle, Yanling Liu, Alan M. Stall, Anja E. Hauser, Yousuke Takahama, Mark C. Dessing, Gergely Toldi, Klaus Warnatz, Raghav Palankar, Sussan Nourshargh, Enrico Lugli, Bimba F. Hoyer, Pleun Hombrink, Bartek Rajwa, Sarah Warth, Isabel Panse, Rachael C. Walker, Silvia Piconese, Andrew Filby, Pärt Peterson, Kilian Schober, Silvia Della Bella, Leonie Wegener, Merle Stein, Anne Cooke, Alessandro Moretta, Deborah Kienhöfer, Andrea Cossarizza, Hyun-Dong Chang, Konrad von Volkmann, Jessica P. Houston, Mübeccel Akdis, Andreas Grützkau, Tristan Holland, Jakob Zimmermann, Jonni S. Moore, Dirk Mielenz, Iain B. McInnes, Bo Huang, Paulo Vieira, Thomas Kroneis, Tobit Steinmetz, Kerstin Juelke, Sharon Sanderson, James V. Watson, Srijit Khan, Sally A. Quataert, Winfried F. Pickl, Annika Wiedemann, Sara De Biasi, Andreas Radbruch, James B. Wing, Susann Müller, Ton N. Schumacher, Katy Rezvani, Gloria Martrus, Alexander Scheffold, Toralf Kaiser, Carlo Pucillo, Lara Gibellini, Anna Rubartelli, Qingyu Cheng, Luca Battistini, David Mirrer, David W. Galbraith, Giovanna Borsellino, Ryan R. Brinkman, Tim R. Mosmann, Laura G. Rico, Anita Dreher, Désirée Kunkel, Francesco Annunziato, Pia Kvistborg, Andrea Gori, Chiara Romagnani, Anat Shemer, Toshinori Nakayama, Francisco Sala-de-Oyanguren, Attila Tárnok, Alfonso Blanco, Anna Iannone, Giuseppe Matarese, Thomas Dörner, Virginia Litwin, Michael Lohoff, Petra Bacher, Jordi Petriz, Lorenzo Moretta, Götz R. A. Ehrhardt, Qianjun Zhang, Andrea Cavani, Barry Moran, Christian Maueröder, Immanuel Andrä, Dirk H. Busch, Joe Trotter, Timothy R D J Radstake, Stipan Jonjić, Fritz Melchers, Hans-Martin Jäck, Beatriz Jávega, Gerald Willimsky, Martin Büscher, Henrik E. Mei, Christine S. Falk, Zhigang Tian, Martin Herrmann, Alice Yue, Steffen Jung, Bart Everts, Frank A. Schildberg, John Bellamy Foster, Giovanna Lombardi, Milena Nasi, John P. Nolan, Todd A. Fehniger, Francesco Dieli, Steffen Schmitt, Andreas Dolf, A. Graham Pockley, Claudia Berek, Josef Spidlen, Megan K. Levings, Werner Müller, Baerbel Keller, René A. W. van Lier, Daisy Philips, Susanne Ziegler, Christian Kurts, Malgorzata J. Podolska, Jürgen Ruland, David Voehringer, Kenneth M. Murphy, Marlous van der Braber, Maria Dolores García-Godoy, Sabine Baumgart, Yi Zhao, Antonio Cosma, Falk Hiepe, Charlotte Esser, Pablo Engel, Marcello Veldhoen, Irmgard Förster, Amy E. Lovett-Racke, Günnur Deniz, Burkhard Ludewig, Esther Schimisky, Cristiano Scottà, Marcello Pinti, Jonathan Rebhahn, Regina Stark, Mario Clerici, Liping Yu, Shimon Sakaguchi, Derek Davies, Anna Katharina Simon, Lorenzo Cosmi, Gabriele Multhoff, Kamran Ghoreschi, Quirin Hammer, Henning Ulrich, J. Paul Robinson, Yvonne Samstag, Olivier Lantz, Hannes Stockinger, Xuetao Cao, Simon Fillatreau, David L. Haviland, Natalio Garbi, C. Neudörfl, Kingston H. G. Mills, Salvador Vento-Asturias, Christian Peth, Philip E. Boulais, Diether J. Recktenwald, Burkhard Becher, Tomas Kalina, Michael D. Leipold, Christoph Goettlinger, Gemma A. Foulds, Jane L. Grogan, Axel R. Schulz, James P. Di Santo, Matthias Schiemann, Michael D. Ward, Britta Engelhardt, Birgit Sawitzki, Annette Oxenius, Carl S. Goodyear, Salomé LeibundGut-Landmann, Wolfgang Beisker, Sue Chow, Carsten Watzl, Marie Follo, Erik Lubberts, Peter Wurst, Thomas Schüler, Andreas Diefenbach, Wolfgang Bauer, Hans-Dieter Volk, Luis E. Muñoz, Elmar Endl, Genny Del Zotto, José-Enrique O'Connor, Mairi McGrath, Paul S. Frenette, Dipartimento di Scienze Biomediche, Università degli Studi di Modena e Reggio Emilia (UNIMORE), Cell Biology, Klinik für Dermatologie, Venerologie und Allergologie, Department of Internal Medicine, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI)-DENOTHE Center, Neuroimmunology Unit, Santa Lucia Foundation (IRCCS), Inorganic Chemistry II, Universität Bayreuth, Caprotec Bioanalytics GmbH, International Occultation Timing Association European Section (IOTA ES), International Occultation Timing Association European Section, Institut der Leibniz-Gemeinschaft, Berlin, Fondazione Santa Lucia (IRCCS), Terry Fox Laboratory, BC Cancer Agency (BCCRC)-British Columbia Cancer Agency Research Centre, Department of Immunology, Chinese Academy of Medical Sciences, Fondazione Don Carlo Gnocchi, Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Experimental Immunology Unit, Dept. of Oncology, DIBIT San Raffaele Scientific Institute, Département d'Immunologie - Department of Immunology, Institut Pasteur [Paris], Charité Hospital, Humboldt-Universität zu Berlin, Universitat de Barcelona (UB), Rheumatologie, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Department of Histology and Embryology, University of Rijeka, Weizmann Institute of Science [Rehovot, Israël], Régulation des Infections Rétrovirales, Institutes of Molecular Medicine and Experimental Immunology, University of Bonn, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), Institute of Virology [Zürich], College of Food Science and Technology [Shangai], Shanghai Ocean University, Institute for Medical Microbiology and Hygiene, University of Marburg, Centre for Transplantation, King's College London (MRC), Guy's Hospital [London], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Institute, Heinrich Pette Institute [Hamburg], Institute of Translational Medicine, Department of Medicine Huddinge, Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm]-Lipid Laboratory, Università di Genova, Dipartimento di Medicina Sperimentale, Department of Environmental Microbiology, Helmholtz Zentrum für Umweltforschung = Helmholtz Centre for Environmental Research (UFZ), Experimental Immunology, Helmholtz Centre for Infection Research (HZI), Viral Immunobiology, Universität Zürich [Zürich] = University of Zurich (UZH)-Institute of Experimental Immunology [Zurich], Department of Radiation Oncology [Munich], Ludwig-Maximilians-Universität München (LMU), Department of Mathematics and Statistics, American University, William Harvey Research Institute, Barts and the London Medical School, Cytometry Laboratories and School of Veterinary Medicine, Purdue University [West Lafayette], Osaka University [Osaka], FACS and Array Core Facility, Johannes Gutenberg - Universität Mainz (JGU), Institute for Cognitive Science, University of Osnabrueck, Department of Molecular Immunology, Medizinische Universität Wien = Medical University of Vienna, Universität Leipzig [Leipzig], Institute of Immunology, School of Life Sciences-University of Science & Technology of China [Suzhou], Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Immunology, Processus de Transfert et d'Echanges dans l'Environnement - EA 3819 (PROTEE), Université de Toulon (UTLN), Heinrich-Pette-Institut, Leibniz Institute for Experimental Virology, Enrico Lugli and Pratip K. Chattopadhyay were supported by grants from the Fondazione Cariplo (Grant Ricerca Biomedica 2012/0683), the Italian Ministry of Health (Bando Giovani Ricercatori GR-2011-02347324) and the European Union Marie Curie Career Integration Grant 322093 (all to E.L.). E.L. and P.K.C. are International Society for the Advancement of Cytometry (ISAC) Marylou Ingram scholars. Alice Yue and Ryan R. Brinkman were funded by Genome BC and NSERC. Klaus Warnatz received funding from the German Federal Ministry of Education and Research (BMBF 01EO1303) and the Deutsche Forschungsgemeinschaft (DECIDE, DFG WA 1597/4-1 and the TRR130). The Jung laboratory is supported by funds of the ERC and ISF. Henrik Mei is a 2017-2021 ISAC scholar. Antonio Cosma is supported by the French government program: 'Investissement d'avenir: Equipements d'Excellence' (EQUIPEX)-2010 FlowCyTech, Grant number: ANR-10-EQPX-02-01. Henrik Mei is supported by the Deutsche Forschungsgemeinschaft (DFG, grants Me3644/5-1 and TRR130/TP24)., Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE), Università degli Studi di Firenze = University of Florence (UniFI)-DENOTHE Center, Institut Pasteur [Paris] (IP), Humboldt University Of Berlin, Universität Bonn = University of Bonn, Università degli studi di Genova = University of Genoa (UniGe), Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Universität Leipzig, Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Obstetrics & Gynecology, Rheumatology, Pediatrics, Landsteiner Laboratory, Other departments, AII - Inflammatory diseases, Università di Modena e Reggio Emilia, DENOTHE Center-University of Florence, Santa Lucia Foundation ( IRCCS ), International Occultation Timing Association European Section ( IOTA ES ), Fondazione Santa Lucia ( IRCCS ), BC Cancer Agency ( BCCRC ) -British Columbia Cancer Agency Research Centre, Fondazione don Carlo Gnocchi, Fondazione IRCCS, Immunologie des Maladies Virales et Autoimmunes ( IMVA - U1184 ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Département d'Immunologie, Humboldt Universität zu Berlin, Universitat de Barcelona ( UB ), Charité, Weizmann Institute of Science, Université de Bonn, Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Singapore Immunology Network ( SIgN ), Agency for Science Technology and Research, College of Food Science and Technology, Centre for Transplantation, King's College London ( MRC ), Erasmus MC University Medical Center, Helmholtz Centre for Environmental Research ( UFZ ), Helmholtz Centre for Infection Research ( HZI ), University of Zürich [Zürich] ( UZH ) -Institute of Experimental Immunology [Zurich], Ludwig-Maximilians-Universität München, Johannes Gutenberg - Universität Mainz ( JGU ), Medical University of Vienna, Lymphopoïèse, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Johannes Gutenberg - University of Mainz ( JGU ), Processus de Transfert et d'Echanges dans l'Environnement - EA 3819 ( PROTEE ), Université de Toulon ( UTLN ), Universita degli studi di Genova, Cossarizza, Andrea, Chang, Hyun-Dong, Radbruch, Andrea, Akdis, Mübeccel, Andrä, Immanuel, Annunziato, Francesco, Bacher, Petra, Barnaba, Vincenzo, Battistini, Luca, Bauer, Wolfgang M., Baumgart, Sabine, Becher, Burkhard, Beisker, Wolfgang, Berek, Claudia, Blanco, Alfonso, Borsellino, Giovanna, Boulais, Philip E., Brinkman, Ryan R., Büscher, Martin, Busch, Dirk H., Bushnell, Timothy P., Cao, Xuetao, Cavani, Andrea, Chattopadhyay, Pratip K., Cheng, Qingyu, Chow, Sue, Clerici, Mario, Cooke, Anne, Cosma, Antonio, Cosmi, Lorenzo, Cumano, Ana, Dang, Van Duc, Davies, Derek, De Biasi, Sara, Del Zotto, Genny, Della Bella, Silvia, Dellabona, Paolo, Deniz, Günnur, Dessing, Mark, Diefenbach, Andrea, Di Santo, Jame, Dieli, Francesco, Dolf, Andrea, Donnenberg, Vera S., Dörner, Thoma, Ehrhardt, Götz R. A., Endl, Elmar, Engel, Pablo, Engelhardt, Britta, Esser, Charlotte, Everts, Bart, Dreher, Anita, Falk, Christine S., Fehniger, Todd A., Filby, Andrew, Fillatreau, Simon, Follo, Marie, Förster, Irmgard, Foster, John, Foulds, Gemma A., Frenette, Paul S., Galbraith, David, Garbi, Natalio, García-Godoy, Maria Dolore, Geginat, Jen, Ghoreschi, Kamran, Gibellini, Lara, Goettlinger, Christoph, Goodyear, Carl S., Gori, Andrea, Grogan, Jane, Gross, Mor, Grützkau, Andrea, Grummitt, Daryl, Hahn, Jona, Hammer, Quirin, Hauser, Anja E., Haviland, David L., Hedley, David, Herrera, Guadalupe, Herrmann, Martin, Hiepe, Falk, Holland, Tristan, Hombrink, Pleun, Houston, Jessica P., Hoyer, Bimba F., Huang, Bo, Hunter, Christopher A., Iannone, Anna, Jäck, Hans-Martin, Jávega, Beatriz, Jonjic, Stipan, Juelke, Kerstin, Jung, Steffen, Kaiser, Toralf, Kalina, Toma, Keller, Baerbel, Khan, Srijit, Kienhöfer, Deborah, Kroneis, Thoma, Kunkel, Désirée, Kurts, Christian, Kvistborg, Pia, Lannigan, Joanne, Lantz, Olivier, Larbi, Ani, LeibundGut-Landmann, Salome, Leipold, Michael D., Levings, Megan K., Litwin, Virginia, Liu, Yanling, Lohoff, Michael, Lombardi, Giovanna, Lopez, Lilly, Lovett-Racke, Amy, Lubberts, Erik, Ludewig, Burkhard, Lugli, Enrico, Maecker, Holden T., Martrus, Glòria, Matarese, Giuseppe, Maueröder, Christian, Mcgrath, Mairi, Mcinnes, Iain, Mei, Henrik E., Melchers, Fritz, Melzer, Susanne, Mielenz, Dirk, Mills, Kingston, Mirrer, David, Mjösberg, Jenny, Moore, Jonni, Moran, Barry, Moretta, Alessandro, Moretta, Lorenzo, Mosmann, Tim R., Müller, Susann, Müller, Werner, Münz, Christian, Multhoff, Gabriele, Munoz, Luis Enrique, Murphy, Kenneth M., Nakayama, Toshinori, Nasi, Milena, Neudörfl, Christine, Nolan, John, Nourshargh, Sussan, O'Connor, José-Enrique, Ouyang, Wenjun, Oxenius, Annette, Palankar, Raghav, Panse, Isabel, Peterson, Pärt, Peth, Christian, Petriz, Jordi, Philips, Daisy, Pickl, Winfried, Piconese, Silvia, Pinti, Marcello, Pockley, A. Graham, Podolska, Malgorzata Justyna, Pucillo, Carlo, Quataert, Sally A., Radstake, Timothy R. D. J., Rajwa, Bartek, Rebhahn, Jonathan A., Recktenwald, Diether, Remmerswaal, Ester B. M., Rezvani, Katy, Rico, Laura G., Robinson, J. Paul, Romagnani, Chiara, Rubartelli, Anna, Ruckert, Beate, Ruland, Jürgen, Sakaguchi, Shimon, Sala-de-Oyanguren, Francisco, Samstag, Yvonne, Sanderson, Sharon, Sawitzki, Birgit, Scheffold, Alexander, Schiemann, Matthia, Schildberg, Frank, Schimisky, Esther, Schmid, Stephan A., Schmitt, Steffen, Schober, Kilian, Schüler, Thoma, Schulz, Axel Ronald, Schumacher, Ton, Scotta, Cristiano, Shankey, T. Vincent, Shemer, Anat, Simon, Anna-Katharina, Spidlen, Josef, Stall, Alan M., Stark, Regina, Stehle, Christina, Stein, Merle, Steinmetz, Tobit, Stockinger, Hanne, Takahama, Yousuke, Tarnok, Attila, Tian, Zhigang, Toldi, Gergely, Tornack, Julia, Traggiai, Elisabetta, Trotter, Joe, Ulrich, Henning, van der Braber, Marlou, van Lier, René A. W., Veldhoen, Marcello, Vento-Asturias, Salvador, Vieira, Paulo, Voehringer, David, Volk, Hans-Dieter, von Volkmann, Konrad, Waisman, Ari, Walker, Rachael, Ward, Michael D., Warnatz, Klau, Warth, Sarah, Watson, James V., Watzl, Carsten, Wegener, Leonie, Wiedemann, Annika, Wienands, Jürgen, Willimsky, Gerald, Wing, Jame, Wurst, Peter, Yu, Liping, Yue, Alice, Zhang, Qianjun, Zhao, Yi, Ziegler, Susanne, Zimmermann, Jakob, Cossarizza, A., Chang, H., Radbruch, A., Akdis, M., Andrã¤, I., Annunziato, F., Bacher, P., Barnaba, V., Battistini, L., Bauer, W., Baumgart, S., Becher, B., Beisker, W., Berek, C., Blanco, A., Borsellino, G., Boulais, P., Brinkman, R., Bã¼scher, M., Busch, D., Bushnell, T., Cao, X., Cavani, A., Chattopadhyay, P., Cheng, Q., Chow, S., Clerici, M., Cooke, A., Cosma, A., Cosmi, L., Cumano, A., Dang, V., Davies, D., De Biasi, S., Del Zotto, G., Della Bella, S., Dellabona, P., Deniz, G., Dessing, M., Diefenbach, A., Di Santo, J., Dieli, F., Dolf, A., Donnenberg, V., Dã¶rner, T., Ehrhardt, G., Endl, E., Engel, P., Engelhardt, B., Esser, C., Everts, B., Dreher, A., Falk, C., Fehniger, T., Filby, A., Fillatreau, S., Follo, M., Fã¶rster, I., Foster, J., Foulds, G., Frenette, P., Galbraith, D., Garbi, N., GarcÃa-Godoy, M., Geginat, J., Ghoreschi, K., Gibellini, L., Goettlinger, C., Goodyear, C., Gori, A., Grogan, J., Gross, M., Grã¼tzkau, A., Grummitt, D., Hahn, J., Hammer, Q., Hauser, A., Haviland, D., Hedley, D., Herrera, G., Herrmann, M., Hiepe, F., Holland, T., Hombrink, P., Houston, J., Hoyer, B., Huang, B., Hunter, C., Iannone, A., Jã¤ck, H., Jã¡vega, B., Jonjic, S., Juelke, K., Jung, S., Kaiser, T., Kalina, T., Keller, B., Khan, S., Kienhã¶fer, D., Kroneis, T., Kunkel, D., Kurts, C., Kvistborg, P., Lannigan, J., Lantz, O., Larbi, A., LeibundGut-Landmann, S., Leipold, M., Levings, M., Litwin, V., Liu, Y., Lohoff, M., Lombardi, G., Lopez, L., Lovett-Racke, A., Lubberts, E., Ludewig, B., Lugli, E., Maecker, H., Martrus, G., Matarese, G., Mauerã¶der, C., Mcgrath, M., Mcinnes, I., Mei, H., Melchers, F., Melzer, S., Mielenz, D., Mills, K., Mirrer, D., Mjã¶sberg, J., Moore, J., Moran, B., Moretta, A., Moretta, L., Mosmann, T., Mã¼ller, S., Mã¼ller, W., Mã¼nz, C., Multhoff, G., Munoz, L., Murphy, K., Nakayama, T., Nasi, M., Neudã¶rfl, C., Nolan, J., Nourshargh, S., O'Connor, J., Ouyang, W., Oxenius, A., Palankar, R., Panse, I., Peterson, P., Peth, C., Petriz, J., Philips, D., Pickl, W., Piconese, S., Pinti, M., Pockley, A., Podolska, M., Pucillo, C., Quataert, S., Radstake, T., Rajwa, B., Rebhahn, J., Recktenwald, D., Remmerswaal, E., Rezvani, K., Rico, L., Robinson, J., Romagnani, C., Rubartelli, A., Ruckert, B., Ruland, J., Sakaguchi, S., Sala-de-Oyanguren, F., Samstag, Y., Sanderson, S., Sawitzki, B., Scheffold, A., Schiemann, M., Schildberg, F., Schimisky, E., Schmid, S., Schmitt, S., Schober, K., Schã¼ler, T., Schulz, A., Schumacher, T., Scotta, C., Shankey, T., Shemer, A., Simon, A., Spidlen, J., Stall, A., Stark, R., Stehle, C., Stein, M., Steinmetz, T., Stockinger, H., Takahama, Y., Tarnok, A., Tian, Z., Toldi, G., Tornack, J., Traggiai, E., Trotter, J., Ulrich, H., van der Braber, M., van Lier, R., Veldhoen, M., Vento-Asturias, S., Vieira, P., Voehringer, D., Volk, H., von Volkmann, K., Waisman, A., Walker, R., Ward, M., Warnatz, K., Warth, S., Watson, J., Watzl, C., Wegener, L., Wiedemann, A., Wienands, J., Willimsky, G., Wing, J., Wurst, P., Liping, Y., Yue, A., Zhang, Q., Zhao, Y., Ziegler, S., and Zimmermann, J.
Subjects: 0301 basic medicine, T-Lymphocytes, Cell Separation, T cell precursors, 0302 clinical medicine, Immunophenotyping, Human lymphopoiesis, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Immunology and Allergy, Non-U.S. Gov't, Immunologic Technique, medicine.diagnostic_test, Research Support, Non-U.S. Gov't, virus diseases, hemic and immune systems, False Positive Reaction, Cell sorting, Flow Cytometry, natural killer and innate lymphoid cells differentiation, 3. Good health, Research Design, [SDV.IMM]Life Sciences [q-bio]/Immunology, Human, Quality Control, medicine.drug_class, Immunology, Animals, Cell Proliferation, DNA, False Positive Reactions, Humans, RNA, Software, Guidelines as Topic, Immunologic Techniques, chemical and pharmacologic phenomena, Computational biology, Biology, Monoclonal antibody, Research Support, Article, Flow cytometry, N.I.H, 03 medical and health sciences, Immune system, Research Support, N.I.H., Extramural, medicine, early lymphoid progenitors, Journal Article, Mass cytometry, IMUNOLOGIA, Animal, Extramural, B cell ontogeny, 030104 developmental biology, T-Lymphocyte, Cytometry, 030215 immunology
Abstract: The marriage between immunology and cytometry is one of the most stable and productive in the recent history of science. A rapid search in PubMed shows that, as of July 2017, using “flow cytometry immunology” as a search term yields more than 68 000 articles, the first of which, interestingly, is not about lymphocytes. It might be stated that, after a short engagement, the exchange of the wedding rings between immunology and cytometry officially occurred when the idea to link fluorochromes to monoclonal antibodies came about. After this, recognizing different types of cells became relatively easy and feasible not only by using a simple fluorescence microscope, but also by a complex and sometimes esoteric instrument, the flow cytometer that is able to count hundreds of cells in a single second, and can provide repetitive results in a tireless manner. Given this, the possibility to analyse immune phenotypes in a variety of clinical conditions has changed the use of the flow cytometer, which was incidentally invented in the late 1960s to measure cellular DNA by using intercalating dyes, such as ethidium bromide. The epidemics of HIV/AIDS in the 1980s then gave a dramatic impulse to the technology of counting specific cells, since it became clear that the quantification of the number of peripheral blood CD4+ T cells was crucial to follow the course of the infection, and eventually for monitoring the therapy. As a consequence, the development of flow cytometers that had to be easy-to-use in all clinical laboratories helped to widely disseminate this technology. Nowadays, it is rare to find an immunological paper or read a conference abstract in which the authors did not use flow cytometry as the main tool to dissect the immune system and identify its fine and complex functions. Of note, recent developments have created the sophisticated technology of mass cytometry, which is able to simultaneously identify dozens of molecules at the single cell level and allows us to better understand the complexity and beauty of the immune system.
Published: 2017

35. Sec22b is a critical and non-redundant regulator of plasma cell maintenance

Author: Amélie Bonaud, Laetitia Gargowitsch, Simon M. Gilbert, Elanchezhian Rajan, Pablo Canales-Herrerias, Daniel Stockholm, Nabila F. Rahman, Mark O. Collins, Hakan Taskiran, Danika L. Hill, Andres Alloatti, Nagham Alouche, Stéphanie Balor, Vanessa Soldan, Daniel Gillet, Julien Barbier, Françoise Bachelerie, Kenneth G. C. Smith, Julia Jellusova, Pierre Bruhns, Sebastian Amigorena, Karl Balabanian, Michelle A. Linterman, Andrew A. Peden, Marion Espéli, Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Cité (UPCité), Microenvironnement des niches tumorales (CNRS GDR 3697 Micronit ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Inflammation, microbiome, immunosurveillance (MI2), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, University of Cambridge [UK] (CAM), University of Sheffield [Sheffield], Anticorps en thérapie et pathologie - Antibodies in Therapy and Pathology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), School of Psychology [Cardiff University], Cardiff University, Technische Universität München = Technical University of Munich (TUM), Max Planck Institute of Immunobiology and Epigenetics (MPI-IE), Max-Planck-Gesellschaft, The Babraham Institute [Cambridge, UK], Monash University [Melbourne], Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Universidad Nacional de Rosario [Santa Fe], Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO) (SIMoS), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), ANR-19-CE15-0019,PC-SEC,Impact des SNARE sur la biologie des plasmocytes(2019), ANR-14-ACHN-0008,AUTO-PLASMO,Analyse integrative de la biologie des plasmocytes normaux et pathologiques(2014), ANR-17-CE14-0019,OSTEOVALYMPH,Autocrinie et paracrinie de l'axe de signalisation CXCL12/CXCR4-CXCR7 dans la niche ostéo-vasculaire: impact sur la spécification et l'engagement lymphoïde des cellules souches hématopoïétiques(2017), ANR-18-CE15-0001,Autoimmuni-B,Etude de la rupture de tolérance dans une maladie humaine autoimmune médiée par les lymphocytes B(2018), The study was supported by the Laboratory of Excellence in Research on Medication and Innovative Therapeutics (LabEx LERMIT) (M.E. and K.B.), an ANR JCJC grant (ANR-19-CE15-0019-01), an ANR @RAction grant (ANR-14-ACHN-0008), a 'Fondation ARC pour la recherche sur le cancer' grant (P JA20181208173), and a grant from IdEx Université Paris-Cité (ANR-18-IDEX-0001) to M.E., and an ANR PRC grant (ANR-17-CE14-0019) and an INCa grant (PRT-K 2017) to K.B. P.B. acknowledges funding from the French National Research Agency grant ANR-18-CE15-0001 project Autoimmuni-B, by the Institut Carnot Pasteur Microbes et Santé grant ANR-11-CARN-0017-01, the Institut Pasteur, and the Institut National de la Santé et de la Recherche Médicale (INSERM). M.A.L. is supported by Biotechnology and Biological Sciences Research Council (BBS/E/B/000C0427, BBS/E/B/000C0428, and the Campus Capability Core Grant to the Babraham Institute). A.A.P. and M.O.C. were supported by a grant from the Biotechnology and Biological Sciences Research Council (BB/L022389/1). D.L.H. is supported by a National Health and Medical Research Council Australia Early-Career Fellowship (APP1139911). N.A. was supported by a PhD fellowship from the French Ministry for education and by a fourth year PhD fellowship from the 'Fondation ARC pour la recherche sur le cancer.' P.C.-H. was supported partly by a stipend from the Pasteur-Paris University (PPU) International PhD program, and by a fellowship from the French Fondation pour la Recherche Médicale (FRM). K.G.C.S. was supported by the Wellcome Trust (Programme Grant Number 083650/Z/07/Z). J.J’s research is supported by the German Research Foundation project number: 419193696 and through the CRC1335. H.T. is supported through the graduate school of the Max Planck Institute for Immunobiology and Epigenetics (IMPRS-IE) and through the CRC1335. The 'EMiLy' U1160 INSERM unit is a member of the OPALE Carnot institute, The Organization for Partnerships in Leukemia (Institut Carnot OPALE, Institut de Recherche Saint-Louis, Hôpital Saint-Louis, Paris, France. Web: www.opale.org. Email: contact@opale.org)., ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), Bonaud, Amélie [0000-0002-4153-9171], Rajan, Elanchezhian [0000-0002-6257-3678], Canales-Herrerias, Pablo [0000-0002-1865-6476], Stockholm, Daniel [0000-0002-5069-5256], Collins, Mark O [0000-0002-7656-4975], Taskiran, Hakan [0000-0002-2690-3887], Alloatti, Andres [0000-0003-0555-0653], Gillet, Daniel [0000-0003-0477-3599], Bruhns, Pierre [0000-0002-4709-8936], Balabanian, Karl [0000-0002-0534-3198], Linterman, Michelle A [0000-0001-6047-1996], Peden, Andrew A [0000-0003-0144-7712], Espéli, Marion [0000-0001-5005-1664], and Apollo - University of Cambridge Repository
Subjects: R-SNARE Proteins, mitochondria, Mice, endoplasmic reticulum, Multidisciplinary, plasma cell, SNARE, antibody, [SDV]Life Sciences [q-bio], Plasma Cells, Animals, Biological Transport, SNARE Proteins
Abstract: Despite the essential role of plasma cells in health and disease, the cellular mechanisms controlling their survival and secretory capacity are still poorly understood. Here, we identified the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) Sec22b as a unique and critical regulator of plasma cell maintenance and function. In the absence of Sec22b, plasma cells were hardly detectable and serum antibody titers were dramatically reduced. Accordingly, Sec22b -deficient mice fail to mount a protective immune response. At the mechanistic level, we demonstrated that Sec22b contributes to efficient antibody secretion and is a central regulator of plasma cell maintenance through the regulation of their transcriptional identity and of the morphology of the endoplasmic reticulum and mitochondria. Altogether, our results unveil an essential and nonredundant role for Sec22b as a regulator of plasma cell fitness and of the humoral immune response.
Published: 2023

36. In Vitro and In Vivo Analysis of the Gram-Negative Bacteria-Derived Riboflavin Precursor Derivatives Activating Mouse MAIT Cells

Author: Frédéric Schmidt, Claire Soudais, Mireille Hervé, Stéphanie Bessoles, Didier Blanot, Lionel Le Bourhis, Fatoumata Samassa, Olivier Lantz, Manal Sarkis, Dominique Mengin-Lecreulx, Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Enveloppes Bactériennes et Antibiotiques, Département Microbiologie ( Dpt Microbio ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Département de Chimie, Institut Curie, Unité Mixte de Recherche 176, Institut Curie, Enveloppes Bactériennes et Antibiotiques ( ENVBAC ), Immunité et cancer (U932), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5), Département Microbiologie (Dpt Microbio), Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Institut de biochimie et biophysique moléculaire et cellulaire (IBBMC), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Chimie biologique des membranes et ciblage thérapeutique (CBMCT - UMR 3666 / U1143), Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Enveloppes Bactériennes et Antibiotiques (ENVBAC), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris], Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), and Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Gram-negative bacteria, Riboflavin, [SDV]Life Sciences [q-bio], Immunology, Cell, Mice, Transgenic, In Vitro Techniques, Ligands, Lymphocyte Activation, medicine.disease_cause, Minor Histocompatibility Antigens, Mice, 03 medical and health sciences, 0302 clinical medicine, In vivo, Escherichia coli, medicine, Animals, [CHIM]Chemical Sciences, Immunology and Allergy, Escherichia coli Infections, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Mucous Membrane, biology, [ SDV ] Life Sciences [q-bio], Histocompatibility Antigens Class I, Flow Cytometry, biology.organism_classification, In vitro, Mice, Inbred C57BL, Disease Models, Animal, medicine.anatomical_structure, Biochemistry, Polyclonal antibodies, biology.protein, Natural Killer T-Cells, Cell activation, Bacteria, 030215 immunology
Abstract: Mucosal-associated invariant T (MAIT) cells recognize microbial compounds presented by the MHC-related 1 (MR1) protein. Although riboflavin precursor derivatives from Gram-positive bacteria have been characterized, some level of ligand heterogeneity has been suggested through the analysis of the MAIT cell TCR repertoire in humans and differential reactivity of human MAIT cell clones according to the bacteria. In this study, using Gram-negative bacteria mutated for the riboflavin biosynthetic pathway, we show a strict correlation between the ability to synthesize the 5-amino-ribityl-uracil riboflavin precursor and to activate polyclonal and quasi-monoclonal mouse MAIT cells. To our knowledge, we show for the first time that the semipurified bacterial fraction and the synthetic ligand activate murine MAIT cells in vitro and in vivo. We describe new MR1 ligands that do not activate MAIT cells but compete with bacterial and synthetic compounds activating MAIT cells, providing the capacity to modulate MAIT cell activation. Through competition experiments, we show that the most active synthetic MAIT cell ligand displays the same functional avidity for MR1 as does the microbial compound. Altogether, these results show that most, if not all, MAIT cell ligands found in Escherichia coli are related to the riboflavin biosynthetic pathway and display very limited heterogeneity.
Published: 2015

37. Monocyte intrinsic NOD2 signalling inhibits pathogenic macrophage differentiation and its loss in inflammatory macrophages improves intestinal inflammation

Author: Camille Chauvin, Daniel Alvarez Simon, Katarina Radulovic, Olivier Boulard, William Laine, Myriam Delacre, Nadine Waldschmitt, Elodie Segura, Jérome Kluza, Mathias Chamaillard, Lionel F. Poulin, CHU Lille, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Centre hospitalier [Valenciennes, Nord], Laboratoire de Physiologie Cellulaire : Canaux ioniques, inflammation et cancer - U 1003 (PHYCELL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Poulin, Lionel, and École Pratique des Hautes Études (EPHE)
Subjects: [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology
Abstract: ObjectiveIt is believed that intestinal recruitment of monocytes from Crohn’s Disease (CD) patients who carry NOD2 risk alleles may repeatedly give rise to recruitment of pathogenic macrophages. We investigated an alternative possibility that NOD2 may rather inhibit their differentiation from intravasating monocytes.DesignThe monocyte fate decision was examined by using germ-free mice, mixed bone marrow chimeras and a culture system yielding macrophages and monocyte-derived dendritic cells (mo-DCs). We next asked whether Nod2 in either monocytes or tissue macrophages have distinct resolving properties in colitis.ResultsDespite a similar abundance of monocytes, the intestinal frequency of mo-DCs from Nod2-deficient mice was lowered independently of the changes in the gut microbiota that are caused by Nod2 deficiency. Similarly, the pool of mo-DCs was poorly reconstituted with mobilized bone marrow Nod2-deficient cells. The use of pharmacological inhibitors revealed that activated NOD2 at an early stage of development dominantly inhibits mTOR-mediated macrophage differentiation in a TNFalpha-dependent manner. These observations were supported by the identification of a TNFalpha-dependent response to MDP that is specifically lost in CD14-expressing blood cells bearing the frameshift mutation in NOD2. Accordingly, loss of NOD2 in monocytes lowers glycolytic reserve, CD115 expression and pro-resolving features. Dietary intake of aryl hydrocarbon receptor (AHR) agonists that promotes mo-DCs generation improves colitis in Nod2-deficient mice to the same extent as what is observed upon macrophage ablation of Nod2.ConclusionNOD2 negatively regulates a macrophage developmental program through a feed-forward loop that could be exploited for overcoming resistance to anti-TNF therapy in CD.Significance of this studyWhat is already known about this subject?Loss of NOD2 function is predisposing to Crohn’s disease.Rapamycin, a serine/THR kinase inhibitor of mammalian target (mTOR) has been reported as potentially effective treatment in discrete subset of CD patients with refractory colitis.The NOD2 protein promotes the chemokine CCL2-dependent recruitment of inflammatory monocytes in response to tissue injury.An accumulation of CCR2-expressing monocytes and inflammatory macrophages is observed within the intestinal mucosa of CD patients including those resistant to anti-TNF therapy.Activated NOD2 enhances proinflammatory activity of CX3CR1intLy6Chi effector monocytes.The monocyte fate toward mo-DCs is orchestrated by the aryl hydrocarbon receptor.What are the new findings?NOD2 has a hierarchically dominant negative role on the mTORC-driven monocyte conversion to inflammatory macrophages independently of the changes in the gut microbiota that are caused by Nod2 deficiency.A defect in monocytes fate at the early stage allow the expansion of pathogenic macrophages in Nod2-deficient mice at the expense of mo-DC.Adoptive transfer of Nod2-deficient monocytes into wild-type mice was sufficient to exacerbate DSS-induced intestinal damage.The glycolytic reserve of monocytes and their ability to respond to M-CSF is lowered upon loss of NOD2 signalling.Deletion of NOD2 in macrophage improves colitis to the same extent as dietary supplementation of AHR agonist in mice.The recognition of the gut microbiota by NOD2 is required for de novo reconstitution of mo-DCs in the lamina propria of the murine intestine, while having minimal effect on the mobilization of their precursors to the intestinal mucosa.How might it impact on clinical practice in the foreseeable future?This study might contribute to the development of novel mTORC-based therapeutic strategies for improving the response to biologics by restoring the ability of circulating monocytes to reconstitute the pool of mo-DCs during homeostatic turnover and upon tissue injury. It may thereby prevent the accumulation of pathogenic macrophages in patients with loss-of-function NOD2 alleles, which fail to respond to anti-TNF and are at greater risk of developing stricturing disease.
Published: 2022

38. Isolated intraocular relapses of primary cerebral lymphomas: An loc network study

Author: Nadia Younan, Carole Soussain, Sylvain Choquet, Nathalie Cassoux, Valérie Touitou, Anna Schmitt, Olivier Chinot, Lucie Oberic, Gandhi Damaj, Roch Houot, Hervé Ghesquières, Kamel Laribi, Guido Ahle, Luc Taillandier, Jérôme Paillassa, Emmanuel Gyan, Fabrice Jardin, Vincent Delwail, Jean‐Pierre Marolleau, Adrian Tempescul, Philippe Agapé, Marie Bourniquel, Fabienne Vacheret, Ibrahim Jdid, Magali Le Garff‐Tavernier, Denis Malaise, Agusti Alentorn, Khê Hoang Xuan, Caroline Houillier, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Curie - Saint Cloud (ICSC), Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche de l'Institut Curie [Paris], Institut Curie [Paris], Institut Bergonié [Bordeaux], UNICANCER, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Timone [CHU - APHM] (TIMONE), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre Hospitalier Le Mans (CH Le Mans), Service de Neurologie [Hôpitaux Civils de Colmar], Hôpitaux Civils Colmar, Centre de Recherche en Automatique de Nancy (CRAN), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Amiens-Picardie, HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), Hopital d'instruction des armées Sainte-Anne [Toulon] (HIA), Service d'Hématologie [CH Perpignan], CH Perpignan, CHU Orléans, Département d'Oncologie Chirurgicale [Institut Curie], Laboratoire d'Imagerie Translationnelle en Oncologie (LITO ), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), DESSAIVRE, Louise, Service d'Onco-neurologie = Département de neurologie 2 [CHU Pitié Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Ophtalmologie [CHU Pitié-Salpêtrière], Service de Biochimie Métabolique [CHU Pitié-Salpêtrière], and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: relapse, Cancer Research, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, primary CNS lymphoma, Oncology, [SDV.CAN] Life Sciences [q-bio]/Cancer, ocular lymphoma, hemic and lymphatic diseases, [SDV.CAN]Life Sciences [q-bio]/Cancer, Hematology, General Medicine, prognosis, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Most relapses of primary central nervous system lymphoma (PCNSL) occur in the brain and are associated with a poor prognosis. Isolated intraocular relapses (IIORs) are rare and poorly described. We retrospectively selected from the French Lymphome Oculo-Cérébral database PCNSL patients who initially presented with cerebral localization and who experienced IIOR during the course of the disease. Of the 1472 patients included in the database, 55 patients presented an IIOR. Their median age was 68 years, and median Karnofsky Performance Status 80. IL-10 levels in the aqueous humor and/or in the vitreous were increased in 42/46 patients. 45/55 patients received systemic chemotherapy, and 11/55 received high-dose chemotherapy with autologous stem cell transplantation (HCT-ASCT) as consolidation treatment. After a median follow-up of 69 months, 42/55 patients had relapsed, including 90% of the patients who did not receive HCT-ASCT at IIOR and 40% of the patients who received HCT-ASCT at IIOR (p 0.001). The first relapse after the initial IIOR was exclusively in the eye in 23/42 patients, and 29/42 patients had a subsequent brain relapse during the course of the disease. The median progression-free survival, brain-free survival and overall survival from IIOR were 12.2, 48.6 and 57.1 months, respectively. Isolated intraocular relapse is not exceptional in the course of PCNSL and deserves systematic ophthalmological follow-up. Its prognosis is much better than the prognosis of brain relapse, with an evolution close to that of primary vitreoretinal lymphoma. With the exception of patients who received HCT-ASCT at IIOR, almost all patients subsequently relapsed, often with other IIORs.
Published: 2022

39. BTG1 inactivation drives lymphomagenesis and promotes lymphoma dissemination through activation of BCAR1

Author: Lorric Delage, Mireille Lambert, Émilie Bardel, Cindy Kundlacz, Dimitri Chartoire, Axel Conchon, Anne-Laure Peugnet, Lucas Gorka, Patrick Auberger, Arnaud Jacquel, Carole Soussain, Olivier Destaing, Henri-Jacques Delecluse, Susanne Delecluse, Samir Merabet, Alexandra Traverse-Glehen, Gilles Salles, Emmanuel Bachy, Marc Billaud, Hervé Ghesquières, Laurent Genestier, Jean-Pierre Rouault, Pierre Sujobert, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Virologie UMR1161 (VIRO), École nationale vétérinaire - Alfort (ENVA)-Laboratoire de santé animale, sites de Maisons-Alfort et de Dozulé, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de Génomique Fonctionnelle de Lyon (IGFL), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), C3M U1065, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Unit F100 [Heidelberg, Allemagne], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Faculty of Biosciences [Heidelberg, Allemagne], Heidelberg University, Microbiology and infectious diseases, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ)-Institut National de la Santé et de la Recherche Médicale (INSERM), German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), CNRS, UMR5242, Inst Genom Fonctionnelle Lyon,Ecole Normale Super, Weill Medical College of Cornell University [New York], Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) (FEMTO-ST), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Génétique moléculaire, signalisation et cancer (GMSC), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), and Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS)
Subjects: [SDV]Life Sciences [q-bio], Immunology, Cell Biology, Hematology, Biochemistry
Abstract: Understanding the functional role of mutated genes in cancer is required to translate the findings of cancer genomics into therapeutic improvement. BTG1 is recurrently mutated in the MCD/C5 subtype of diffuse large B-cell lymphoma (DLBCL), which is associated with extranodal dissemination. Here, we provide evidence that Btg1 knock out accelerates the development of a lethal lymphoproliferative disease driven by Bcl2 overexpression. Furthermore, we show that the scaffolding protein BCAR1 is a BTG1 partner. Moreover, after BTG1 deletion or expression of BTG1 mutations observed in patients with DLBCL, the overactivation of the BCAR1-RAC1 pathway confers increased migration ability in vitro and in vivo. These modifications are targetable with the SRC inhibitor dasatinib, which opens novel therapeutic opportunities in BTG1 mutated DLBCL.
Published: 2022

40. Guidelines for mouse and human DC generation

Author: Manfred B. Lutz, Shafaqat Ali, Cindy Audiger, Stella E. Autenrieth, Luciana Berod, Venetia Bigley, Laura Cyran, Marc Dalod, Jan Dörrie, Diana Dudziak, Georgina Flórez‐Grau, Lucila Giusiano, Gloria J. Godoy, Marion Heuer, Anne B. Krug, Christian H. K. Lehmann, Christian T. Mayer, Shalin H. Naik, Stefanie Scheu, Gerty Schreibelt, Elodie Segura, Kristin Seré, Tim Sparwasser, Jurjen Tel, Huaming Xu, Martin Zenke, University of Würzburg, Institute of Medical Microbiology and Hospital Hygiene (University of Düsseldorf), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], The Walter and Eliza Hall Institute of Medical Research (WEHI), University of Melbourne, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), University of Tübingen, University Medical Center of the Johannes Gutenberg-University Mainz, Newcastle University [Newcastle], Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universitätsklinikum Erlangen [Erlangen], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), University Hospital Erlangen = Uniklinikum Erlangen, Radboud Institute for Molecular Life Sciences [Nijmegen, the Netherlands], Ludwig Maximilian University [Munich] (LMU), Universität Duisburg-Essen = University of Duisburg-Essen [Essen], Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL), Universitätsklinikum RWTH Aachen - University Hospital Aachen [Aachen, Germany] (UKA), Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Eindhoven University of Technology [Eindhoven] (TU/e), University of Duisburg-Essen, and Dalod, Marc
Subjects: In vitro, Immunology, Generation, Immunology and Allergy, endritic cells, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Isolation
Abstract: European journal of immunology (2022). doi:10.1002/eji.202249816, Published by Wiley-VCH, Weinheim
Published: 2022

41. There is a need for a complete consideration of overall movement behaviors for the prevention, treatment, and follow-up of cancer risks and patients

Author: Gaël Ennequin, Lidia Delrieu, Adrien Rossary, Quentin Jacquinot, Fabienne Mougin, David Thivel, Martine Duclos, Laboratoire des Adaptations Métaboliques à l'Exercice en Conditions Physiologiques et Pathologiques (AME2P), Université Clermont Auvergne (UCA)-UFR Sciences et Techniques des Activités Physiques et Sportives - Clermont-Auvergne (UFR STAPS - UCA), Université Clermont Auvergne (UCA)-Université Clermont Auvergne (UCA), Residual Tumor & Response to Treatment Laboratory [Paris] (RT2Lab), Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Nutrition Humaine (UNH), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA), Institut Régional Fédératif du Cancer (IRFC), Université de Bourgogne (UB), Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( UR 3920) (PCVP / CARDIO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), and CHU Clermont-Ferrand
Subjects: treatment, Health Behavior, Public Health, Environmental and Occupational Health, physical activity, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, prevention, sedentary behavior, Neoplasms, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], cancer, Humans, Exercise, Follow-Up Studies
Abstract: International audience; No abstract available
Published: 2022

42. Introduction to the special issue on 'unconventional T cells'

Author: Legoux, François, Lantz, Olivier, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], ANR-10-IDEX-0001-02 PSL, Agence Nationale de la Recherche, ERC-2019-AdG-885435, European Research Council, ANR-16-CE15-0020,MAIT,Biologie des cellules MAIT in vivo en situation normale ou pathologique(2016), and ANR-20-CE15-0028,MAIT-repair,Mécanisme de la fonction de réparation tissulaire des lymphocytes MAIT(2020)
Subjects: T-Lymphocytes, [SDV]Life Sciences [q-bio], Immunology, Humans, Immunology and Allergy
Abstract: International audience
Published: 2022

43. Lentiviral Nef suppresses iron uptake in a strain specific manner through inhibition of Transferrin endocytosis

Author: Miriam Widder, Kristin Höhne, Swantje Gundlach, François-Xavier Gobert, Michael Winkler, Frank Kirchhoff, Anke Heigele, Philippe Benaroch, Michael Schindler, Marcos Vinícius Pereira Gondim, Herwig Koppensteiner, Institute of Virology, German Research Center for Environmental Health-Helmholtz-Zentrum München (HZM), Leibniz Institute for Experimental Virology, Heinrich Pette Institute, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Current address: Martin Luther University Halle-Wittenberg, Internal Medicine IV, Institute of Molecular Virology, Universitätsklinikum Ulm - University Hospital of Ulm, German Primate Center - Deutsches Primatenzentrum -- Leibniz Insitute for Primate Research -- [Göttingen, Allemagne] (GPC - DPZ), Grant of the German Research Foundation (DFG) to MS (SCHI 1073/2-1)., Helmholtz Zentrum München = German Research Center for Environmental Health, Martin-Luther-Universität Halle Wittenberg (MLU), BMC, Ed., German Research Center for Environmental Health-Helmholtz-Zentrum München ( HZM ), Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Ulm University Medical Center, and German Primate Center
Subjects: media_common.quotation_subject, viruses, Iron, Transferrin receptor, Biology, medicine.disease_cause, Endocytosis, HIV, SIV, Nef, Iron homeostasis, AIDS, Lentiviral replication, Macrophages, Gene Products, nef, 03 medical and health sciences, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Virology, Receptors, Transferrin, medicine, Animals, Internalization, 030304 developmental biology, media_common, chemistry.chemical_classification, 0303 health sciences, 030306 microbiology, Research, Simian immunodeficiency virus, Transferrin, CD28, virus diseases, Haplorhini, 3. Good health, Cell biology, [ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Infectious Diseases, chemistry, Viral replication, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Simian Immunodeficiency Virus, Intracellular
Abstract: Background Increased cellular iron levels are associated with high mortality in HIV-1 infection. Moreover iron is an important cofactor for viral replication, raising the question whether highly divergent lentiviruses actively modulate iron homeostasis. Here, we evaluated the effect on cellular iron uptake upon expression of the accessory protein Nef from different lentiviral strains. Results Surface Transferrin receptor (TfR) levels are unaffected by Nef proteins of HIV-1 and its simian precursors but elevated in cells expressing Nefs from most other primate lentiviruses due to reduced TfR internalization. The SIV Nef-mediated reduction of TfR endocytosis is dependent on an N-terminal AP2 binding motif that is not required for downmodulation of CD4, CD28, CD3 or MHCI. Importantly, SIV Nef-induced inhibition of TfR endocytosis leads to the reduction of Transferrin uptake and intracellular iron concentration and is accompanied by attenuated lentiviral replication in macrophages. Conclusion Inhibition of Transferrin and thereby iron uptake by SIV Nef might limit viral replication in myeloid cells. Furthermore, this new SIV Nef function could represent a virus-host adaptation that evolved in natural SIV-infected monkeys.
Published: 2014

44. X-linked primary immunodeficiency associated with hemizygous mutations in the moesin (MSN) gene

Author: Jacek Majewski, Marielle E. van Gijn, Alain Fischer, Geneviève de Saint Basile, Capucine Picard, Nada Jabado, Els Verhoeyen, Sonia Luce, Tayebeh Soheili, Nathalie Lambert, Amandine Durand, Armelle Bohineust, Claire Hivroz, Virginie Gandemer, Farid Ouchani, Chantal Brouzes, Catherine Heijmans, Anne Durandy, Isabelle Pic, Myriam Chouteau, Marina Cavazzana, Virgil A. S. H. Dalm, Nizar Mahlaoui, Aude Magerus-Chatinet, François-Loïc Cosset, Isabelle André-Schmutz, Delphine Monnier, Sven Kracker, Chantal Lagresle-Peyrou, Jean-Louis Stephan, Frédéric Rieux-Laucat, Hanem Sadek, Human Lymphohematopoiesis Laboratory (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Biothérapie [CHU Necker], CHU Necker - Enfants Malades [AP-HP]-Université Paris Descartes - Paris 5 (UPD5)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), McGill University and Genome Quebec Innovation Centre, CHU Necker - Enfants Malades [AP-HP], Center for the Study of Primary Immunodeficiencies [Paris], Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Immunité et cancer (U932), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (Equipe EVIR), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Service d'Hématologie, Immunologie et de Thérapie Cellulaire (HITC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Hôpital Universitaire des Enfants - Reine Fabiola, Dpt of Genetics [Utrecht], University Medical Center [Utrecht], Department of Internal Medicine, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'immuno-hématologie pédiatrique [CHU Necker], CHU Saint-Etienne, the Genome Quebec Innovation Centre, McGill University, Collège de France (CdF), French National Research Agency, French National Institute of Health and Medical Research (INSERM), La Ligue contre le Cancer and La Fondation ARC pour la Recherche sur le Cancer, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Hôpital Universitaire des Enfants Reine Fabiola [Bruxelles, Belgique] (HUDERF), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), McGill University = Université McGill [Montréal, Canada], Collège de France - Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), CIC-BT 502 INSERM, Departement de Biotherapie, Laboratoire d'hématologie ( ERL 8254 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Référence Déficits Immunitaires Héréditaires ( CEREDIH ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre méditérannéen de médecine moléculaire ( C3M ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ), Centre International de Recherche en Infectiologie ( CIRI ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service d'Hématologie, Immunologie et de Thérapie Cellulaire ( HITC ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Collège de France ( CdF ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Chaire Médecine expérimentale (A. Fischer), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Institut Curie-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunology, and Internal Medicine
Subjects: Adult, Male, 0301 basic medicine, Adolescent, Moesin, Immunology, Nonsense mutation, macromolecular substances, CD8-Positive T-Lymphocytes, Biology, Infections, primary immunodeficiency, migration, medicine.disease_cause, ezrin-radixin-moesin protein, Hypogammaglobulinemia, 03 medical and health sciences, Cell Movement, Radixin, Cell Adhesion, Journal Article, medicine, Humans, Immunology and Allergy, Missense mutation, Lymphocyte Count, Child, moesin, Genetic Association Studies, Immunodeficiency, Aged, Chromosomes, Human, X, [SDV.GEN]Life Sciences [q-bio]/Genetics, Mutation, Microfilament Proteins, Immunologic Deficiency Syndromes, Leukopenia, medicine.disease, Pedigree, 3. Good health, adhesion, 030104 developmental biology, Child, Preschool, Cancer research, Primary immunodeficiency, [ SDV.GEN ] Life Sciences [q-bio]/Genetics
Abstract: International audience; BACKGROUND: We investigated 7 male patients (from 5 different families) presenting with profound lymphopenia, hypogammaglobulinemia, fluctuating monocytopenia and neutropenia, a poor immune response to vaccine antigens, and increased susceptibility to bacterial and varicella zoster virus infections. OBJECTIVE: We sought to characterize the genetic defect involved in a new form of X-linked immunodeficiency. METHODS: We performed genetic analyses and an exhaustive phenotypic and functional characterization of the lymphocyte compartment. RESULTS: We observed hemizygous mutations in the moesin (MSN) gene (located on the X chromosome and coding for MSN) in all 7 patients. Six of the latter had the same missense mutation, which led to an amino acid substitution (R171W) in the MSN four-point-one, ezrin, radixin, moesin domain. The seventh patient had a nonsense mutation leading to a premature stop codon mutation (R533X). The naive T-cell counts were particularly low for age, and most CD8(+) T cells expressed the senescence marker CD57. This phenotype was associated with impaired T-cell proliferation, which was rescued by expression of wild-type MSN. MSN-deficient T cells also displayed poor chemokine receptor expression, increased adhesion molecule expression, and altered migration and adhesion capacities. CONCLUSION: Our observations establish a causal link between an ezrin-radixin-moesin protein mutation and a primary immunodeficiency that could be referred to as X-linked moesin-associated immunodeficiency.
Published: 2016

45. The capsids of HIV-1 and HIV-2 determine immune detection of the viral cDNA by the innate sensor cGAS in dendritic cells

Author: Matteo Gentili, Christine Lacabaratz, Ilse Hurbain, Xavier Lahaye, Ahmed El Marjou, Cécile Conrad, Jean-Daniel Lelièvre, Takeshi Satoh, Nicolas Manel, Silvia Cerboni, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Compartimentation et dynamique cellulaires (CDC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Immunologie Clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, This work was supported by Institut Curie, Institut National de la Santé et de la Recherche Médicale (INSERM), ATIP-Avenir program, Agence Nationale de Recherche sur le SIDA (ANRS), Ville de Paris Emergence program, European FP7 Marie Curie Actions, European Research Council, LABEX VRI and LABEX DCBIOL., Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Compartimentation et dynamique cellulaires ( CDC ), Centre National de la Recherche Scientifique ( CNRS ) -INSTITUT CURIE-Université Pierre et Marie Curie - Paris 6 ( UPMC ), Institut Mondor de Recherche Biomédicale ( IMRB ), Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, and Guellaen, Georges
Subjects: MESH : DNA, Complementary, viruses, HIV Infections, MESH : Models, Biological, Genome, MESH: HIV-1, chemistry.chemical_compound, 0302 clinical medicine, MESH: HIV-2, Immunology and Allergy, MESH: Nucleotidyltransferases, MESH: Capsid, MESH : DNA, Viral, Cells, Cultured, MESH : Nucleotidyltransferases, 0303 health sciences, MESH: Dendritic Cells, virus diseases, MESH: HIV Infections, MESH : Immunity, Innate, Nucleotidyltransferases, 3. Good health, Infectious Diseases, Capsid, 030220 oncology & carcinogenesis, MESH: Immunity, Innate, MESH : Capsid, MESH : HIV-2, MESH : HIV-1, MESH: Cells, Cultured, DNA, Complementary, CypA, Immunology, innate antiviral immunity, chemical and pharmacologic phenomena, Biology, Models, Biological, Virus, 03 medical and health sciences, Immune system, Immunity, Complementary DNA, MESH : Cells, Cultured, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : HIV Infections, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Innate immune system, MESH: Humans, HIV-1 capsid, MESH : Humans, MESH: Models, Biological, Dendritic Cells, MESH: DNA, Complementary, biochemical phenomena, metabolism, and nutrition, Virology, Immunity, Innate, MESH: DNA, Viral, Prospects & Overviews, chemistry, MESH : Dendritic Cells, DNA, Viral, HIV-2, HIV-1, cytosolic DNA sensor, DNA, cGAS
Abstract: International audience; HIV-2 is less pathogenic for humans than HIV-1 and might provide partial cross-protection from HIV-1-induced pathology. Although both viruses replicate in the T cells of infected patients, only HIV-2 replicates efficiently in dendritic cells (DCs) and activates innate immune pathways. How HIV is sensed in DC is unknown. Capsid-mutated HIV-2 revealed that sensing by the host requires viral cDNA synthesis, but not nuclear entry or genome integration. The HIV-1 capsid prevented viral cDNA sensing up to integration, allowing the virus to escape innate recognition. In contrast, DCs sensed capsid-mutated HIV-1 and enhanced stimulation of T cells in the absence of productive infection. Finally, we found that DC sensing of HIV-1 and HIV-2 required the DNA sensor cGAS. Thus, the HIV capsid is a determinant of innate sensing of the viral cDNA by cGAS in dendritic cells. This pathway might potentially be harnessed to develop effective vaccines against HIV-1.
Published: 2013

46. Differential Effects of the Cytokine Thymic Stromal Lymphopoietin on Human Dendritic Cell Subsets

Author: Martinez Cingolani, Carolina, Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Sud - Paris XI, Vassili Soumelis, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and STAR, ABES
Subjects: Chimiokines, [SDV.IMM] Life Sciences [q-bio]/Immunology, Cellules dendritiques, Dendritic cells, Sous-populations, Subsets, Lymphopoietine stromale thymique, Thymic stromal lymphopoietin, [SDV.IMM]Life Sciences [q-bio]/Immunology, Humain, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Chemokines, Migration, Human
Abstract: Once activated, Dendritic Cells (DCs) migrate to the lymphoid organs and exert their role as professional antigen presenting cells. They are able to induce the activation and differentiation of naïve T cells into different types of T helper cells. The T cell response must be suited to the type of inflammation. This is ensured by DCs at two levels. First DCs are functionally plastic. This means that their behavior is subdued to the integrated signals coming from the inflammatory microenvironment. Secondly, the DC population is diverse. Indeed, different DC subsets have different functional specializations. My thesis was focused on the differential response of human DC subsets to Thymic stromal lymphopoietin (TSLP). This cytokine is secreted by inflamed skin and epithelia, and strongly activates myeloid DCs. The TSLP-activated DCs secrete the inflammatory chemokines CCL17 and CCL22, prime an inflammatory Th2 response, and have been involved in the pathogenesis of allergic inflammation. By systematically comparing the response of human blood BDCA-1+ and BDCA-3+ DCs to TSLP stimulation we found that both of these DC subsets get activated by TSLP. However TSLP synergizes with TGF-β to induce the differentiation of blood BDCA-1+ and not BDCA-3+ DCs into Langerhans Cells. Moreover, TSLP induces cell migration and chemokine secretion only on the blood BDCA-1+ subset. Further analysis of the mechanisms implicated in TSLP-induced DC migration revealed that TSLP is required to induce DC migration, but this effect is dependent on the expression of a PTX-sensitive chemokine receptor. Overall our results reveal new precursor capacities of blood DC subsets, different functional properties of blood DC subsets stimulated by TSLP and highlight intricate mechanisms underlying TSLP-induced DC migration., Une fois activées, les cellules dendritiques (DCs) migrent dans les organes lymphoïdes ou elles exercent leur rôle de cellules présentatrices d’antigène professionnelles. Elles sont capables d’activer et d’induire la différenciation des lymphocytes T naïfs en différentes sous-populations de lymphocytes T auxiliaires. L’ajustement de la réponse lymphocytaire T au type d’inflammation est assuré par les DCs à deux niveaux. Premièrement, grâce à leur plasticité, les DCs adaptent leur comportement en fonction de la combinaison de signaux issus du microenvironnement inflammatoire. Deuxièmement, il existe différentes sous-populations de cellules dendritiques ayant de différentes spécialisations fonctionnelles.Mon travail de thèse s’est concentré sur l’étude de la diversité des réponses des sous-populations de cellules dendritiques humaines suite à la stimulation par la cytokine lymphopoïetine stromale thymique (TSLP). Cette cytokine est secrétée par les cellules épithéliales et la peau au cours de l’inflammation. La TSLP active principalement les DCs myéloïdes, induisant celles-ci à secréter les chimiokines inflammatoires CCL17 et CCL22. Les DCs activées par la TSLP (TSLP-DCs) induisent une réponse inflammatoire de type Th2, et sont impliquées dans le développement de l’allergie. La comparaison systématique de la réponse à la TSLP par les sous-populations de DCs du sang, BDCA1+ et BDCA3+, nous a permis de montrer que ces deux sous-populations sont activées par la TSLP. Toutefois, nos résultats montrent que la TSLP, en synergie avec le TGF-β, induit la différenciation des DCs BDCA-1+ en cellules de Langerhans, mais pas celle des DCs BDCA-3+. De plus, la TSLP induit la migration cellulaire et la sécrétion de chimiokines seulement chez la sous-population de DCs BDCA-1+. Des analyses complémentaires des mécanismes impliqués dans la migration des DCs BDCA-1+ en réponse à la TSLP révèlent que, d’une part la TSLP est indispensable à l’induction de la migration et d’autre part, qu’un récepteur de chimiokines, sensible à la Toxine Pertussique serait impliqué. Au final, nos résultats révèlent (i) de nouvelles capacités des DCs en tant que cellules précurseurs, (ii) de différentes propriétés fonctionnelles des sous-populations de DCs en réponse à la stimulation par la TSLP, (iii) et démontrent la complexité des mécanismes impliqués dans la migration des DCs induite par la TSLP.
Published: 2013

47. Extrathymic induction of Foxp3⁺ regulatory T cells declines with age in a T-cell intrinsic manner

Author: Carpentier, Maxime, Chappert, Pascal, Kuhn, Chantal, Lalfer, Mélanie, Flament, Héloïse, Burlen-Defranoux, Odile, Lantz, Olivier, Bandeira, Antonio, Malissen, Bernard, Davoust, Jean, Gross, David-Alexandre, Tolérance immunitaire et présentation antigénique: impact en auto-immunité et en transplantation, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunité et cancer (U932), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5), Lymphopoïèse, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie des Populations Lymphocytaires, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), This work was supported by the Association Franc¸aise contre les Myopathies and the Agence Nationale de la Recherche (ANR-11-JSV3). M. Carpentier, P. Chappert, and M. Lalfer were supported by the French Ministry of Research. C. Kuhn was supported by the Fondation pour la Recherche Médicale (FRM)., Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Centre d'Immunologie de Marseille - Luminy ( CIML ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [ SDV.IMM ] Life Sciences [q-bio]/Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, hemic and immune systems, chemical and pharmacologic phenomena
Abstract: International audience; Extrathymically induced Foxp3⁺ regulatory T (Treg) cells contribute to the pool of Treg cells and are implicated in the maintenance of immune tolerance at environmental interfaces. The impact of T-cell senescence on their generation and function is, however, poorly characterized. We report here that steady-state induction of Foxp3 is impaired in aged T cells in vivo. In vitro assays further revealed that this defective generation of Treg cells was independent from the strength of TCR stimulation and arose before T-cell proliferation. Importantly, they also revealed that this impairment of Foxp3 induction is unrelated to known age-related T-cell defects, such as IL-2 secretion impairment, accumulation of activated T-cell populations, or narrowing of the T-cell repertoire. Finally, a loss of extrathymic induction of Foxp3 and tolerance to minor-mismatched skin graft were observed in aged mice treated by nondepleting anti-CD4 antibody. The T-cell intrinsic impairment of Treg-cell generation revealed here highlights age as a key factor to be considered in immune tolerance induction.
Published: 2013

48. Antigen presentation by mouse monocyte-derived cells: Re-evaluating the concept of monocyte-derived dendritic cells

Author: Elodie Segura, Alice Coillard, Immunité et cancer (U932), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], Université Paris sciences et lettres (PSL), and Segura, Elodie
Subjects: 0301 basic medicine, monocyte-derived dendritic cell, T-Lymphocytes, Immunology, Population, Antigen presentation, Inflammation, Biology, Lymphocyte Activation, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Monocytes, Mice, 03 medical and health sciences, 0302 clinical medicine, Antigen, medicine, Animals, Antigens, education, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, Molecular Biology, education.field_of_study, Effector, Monocyte, Cell Differentiation, Dendritic Cells, Dendritic cell, Phenotype, Cell biology, antigen presentation, 030104 developmental biology, medicine.anatomical_structure, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, inflammation, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, monocyte, medicine.symptom, 030215 immunology
Abstract: International audience; Antigen presentation is a key feature of classical dendritic cells (cDCs). Numerous studies have also reported in mouse that, upon inflammation, monocytes enter tissues and differentiate into monocyte-derived DCs (mo-DC) that have the ability to present antigens to T cells. However, a population of inflammatory cDCs sharing phenotypic features with mo-DC has been recently described, challenging the existence of in vivo-generated mo-DC. Here we review studies describing mouse mo-DC in the light of these findings, and evaluate the in vivo evidence for monocyte-derived antigen-presenting cells. We examine the strategies used to demonstrate the monocytic origin of these cells. Finally, we propose that mo-DC play a complementary role to cDCs, by presenting antigens to effector T cells locally in tissues.
Published: 2021

49. In vivo study of MAIT cell tissue repair function

Author: de Poulpiquet Du Halgouet, Anastasia, Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres, Olivier Lantz, and STAR, ABES
Subjects: Réparation, Peau, In vivo, MAIT cells, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.MHEP.DERM] Life Sciences [q-bio]/Human health and pathology/Dermatology, Cellule MAIT, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Repair, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, Skin
Abstract: The mechanical, chemical, or infectious mediated tissue damages affect all epithelial barriers including the skin. The rapid resolution of theses damages is key to recover their integrity and function, it involves the joint action of several immune cells that infiltrate the barrier tissues. The interest surrounding the study of MAIT (mucosal-associated immune T) cells in repair stems from their high frequency in the skin (up to 10% of T cells) and their capacity to rapidly secrete various effector molecules. Recently, it has been shown both in vitro and in vivo that MAIT cells are involved in wound healing. However, the mechanisms that underly this pro-repair function remain elusive. Using the congenic B6-MAITCAST strain (10 times more MAIT cells than the C57BL/6 mice) and an full thickness excision model mimicking the human repair process (Dunn et al., 2013), we aimed at unravelling these mechanisms. With these tools, we first show that MAIT cells accelerates wound closure. Because MAIT cell numbers and frequency increased following injury without increased proliferation, we hypothesized that MAIT cells were recruited to the wound site. Using skin graft experiments we evidenced that, contrary to the resident gdT cells, MAIT cells are rapidly recruited into the inflamed site. The Kaedes mouse (in which local ultraviolet light induces a shift in fluorescence) strain and the use of FTY720 treatment demonstrated that recruited cells transited through the lymph nodes rather than from the surrounding skin. We next investigated whether TCR signaling, via MR1 the MAIT cell antigen presenting molecule, could be necessary both for the recruitment and the tissue repair function. To investigate MAIT cells reliance on TCR signaling, we performed parabiosis of MR1+ and MR1- animals and MR1- skin grafted onto MR1+ animals, and we showed that MAIT cell recruitment was MR1-independent. Instead, the recruitment relied on the CXCL16-CXCR6 signaling, as shown by blocking CXCL16 in vivo and deleting CXCR6 on MAIT cells by CRISPR-Cas9 genetic modification. Adoptive ransfer experiments further demonstrated that wound closure does not depend on a continuous TCR signaling.Concerning their effector function our scRNAseq analysis suggested that MAIT cell repair program was acquired already at steady state in the skin. Additionally, we observed an increase in epithelial tongue length and proliferation within these tongues in the presence of MAIT cells as compared to their absence. Thus, we presupposed that MAIT cells could play a direct effector function on keratinocyte growth. This theory was supported by scRNAseq that showed that signatures associated to amphiregulin-producing pro-repair cells were up-regulated by skin MAIT cells . We observed that amphiregulin produced by PLZF cells was necessary in our model and that MAIT cells increased its production at the protein level following wounding. Transfer experiments of Areg deficient MAIT cells formally demonstrated that Areg produced by MAIT cells was instrumental for promoting wound repair.Overall, our study describes the dynamics of MAIT cells within the skin, the signals they rely on for recruitment and how they promote tissue repair in an MR1 independent manner. It also provides evidence to an Areg mediated mechanism supporting this repair function. These additional insights on MAIT cell biology could provide key therapeutic axes that could help alleviate the pain, discomfort and complications caused by unhealed or poorly healed wounds., Les dommages tissulaires d'origine mécanique, chimique ou infectieuse affectent toutes les barrières épithéliales, y compris la peau. La résolution rapide de ces dommages est essentielle pour que ces barrières recouvrent leur intégrité et fonction, elle implique l'action conjointe de cellules immunitaires infiltrant ces tissus. L'intérêt entourant l'étude des cellules MAIT (cellules T immunitaires associées aux muqueuse) dans la réparation provient de leur fréquence élevée dans la peau (jusqu'à 10% des cellules T) et de leur capacité à sécréter rapidement diverses molécules effectrices. Récemment, il a été démontré à la fois in vitro et in vivo que les cellules MAIT sont impliquées dans la cicatrisation des plaies. Cependant, les mécanismes qui sous-tendent cette fonction pro-réparatrice demeurent inconnus. En utilisant la souche congénique B6-MAITCAST (10 fois plus de cellules MAIT que les souris C57BL/6) et un modèle d'excision mimant le processus de réparation humain (Dunn et al., 2013), nous avons cherché à élucider ces mécanismes. Grâce à ces outils, nous montrons que les cellules MAIT accélèrent la fermeture des plaies. Ayant observé l’augmentation du nombre et de la fréquence des cellules MAIT au sein des plaies sans augmentation de leur prolifération, nous avons émis l'hypothèse qu’elles étaient recrutées. À l’aide de greffe de peau, nous avons mis en évidence que, contrairement aux cellules gdT résidentes, les cellules MAIT sont recrutées au site inflammatoire. La souris Kaedes (où la lumière ultraviolette induit un changement de fluorescence) et le traitement par FTY720 démontrent que les cellules recrutées transitent par les ganglions lymphatiques et ne migrent pas depuis d'autres endroits de la peau. Nous avons ensuite cherché à savoir si la signalisation du TCR, via MR1, la molécule de présentation de l'antigène des cellules MAIT, était nécessaire pour leur recrutement et fonction réparatrice. Pour étudier la dépendance des cellules MAIT à la signalisation TCR, nous avons réalisé une parabiose d'animaux MR1+ et MR1- et une greffe de peau MR1- sur des animaux MR1+, ceci a montré que leur recrutement était MR1 indépendant. Les expériences de blocage de CXCL16 et de suppression génétique de CXCR6 sur les cellules MAIT par CRISPR-Cas9 montrent que le recrutement est dépendant de la signalisation CXCL16-CXCR6. Nos expériences de transfert adoptif démontrent également que la fermeture de la plaie est indépendante de la signalisation du TCR.Concernant leur fonction effectrice, notre analyse scRNAseq suggère que le programme de réparation des cellules MAIT acquis dans la peau à l’état basal. De plus, nous observons qu’en présence des cellules MAIT il y a une augmentation significative de la longueur des langues épithéliales et de la prolifération au sein de ces langues. Ainsi, nous avons présupposé que les cellules MAIT pouvaient agir directement sur la croissance des kératinocytes. Cette théorie est appuyée par le scRNAseq montrant une augmentation de l’expression de signatures associées à des cellules pro-réparatrices produisant de l'amphireguline (Areg) par les cellules MAIT cutanées. Conjointement, nous observons la nécessité de l’Areg produite par les cellules PLZF dans notre modèle et l’augmentation de sa production par les cellules MAIT. Des expériences de transfert de cellules MAIT déficientes en Areg démontrent que l'Areg produite par les cellules MAIT est déterminante pour la réparation des plaies.Dans l'ensemble, notre étude décrit la dynamique des cellules MAIT dans la peau, les signaux sur lesquels elles s'appuient pour leur recrutement et la manière dont elles promeuvent la réparation des tissus. Elle fournit également des preuves d'un mécanisme médié par l'Areg sous-tendant cette fonction. Ces connaissances sur la biologie des cellules MAIT fournissent de nouveaux axes thérapeutiques qui pourraient atténuer la douleur, l'inconfort et les complications causés par les plaies non ou mal cicatrisées.
Published: 2022

50. Microtubules restrict F-actin polymerization to the immune synapse via GEF-H1 to maintain polarity in lymphocytes

Author: Judith Pineau, Léa Pinon, Olivier Mesdjian, Jacques Fattaccioli, Ana-Maria Lennon Duménil, Paolo Pierobon, Centre Interdisciplinaire de Nanoscience de Marseille (CINaM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Processus d'Activation Sélective par Transfert d'Energie Uni-électronique ou Radiatif (UMR 8640) (PASTEUR), Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Pierre-Gilles de Gennes pour la Microfluidique, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Paris sciences et lettres (PSL)
Subjects: B-Lymphocytes, General Immunology and Microbiology, General Neuroscience, General Medicine, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Microtubules, Actins, General Biochemistry, Genetics and Molecular Biology, Polymerization, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Mice, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Synapses, Animals, Rho Guanine Nucleotide Exchange Factors
Abstract: Immune synapse formation is a key step for lymphocyte activation. In B lymphocytes, the immune synapse controls the production of high-affinity antibodies, thereby defining the efficiency of humoral immune responses. While the key roles played by both the actin and microtubule cytoskeletons in the formation and function of the immune synapse have become increasingly clear, how the different events involved in synapse formation are coordinated in space and time by actin-microtubule interactions is not understood. Using a microfluidic pairing device, we studied with unprecedented resolution the dynamics of the various events leading to immune synapse formation and maintenance. Our results identify two groups of events, local and global dominated by actin and microtubules dynamics, respectively. They further highlight an unexpected role for microtubules and the GEF-H1-RhoA axis in restricting F-actin polymerization at the immune synapse to define the cell polarity axis, allowing the formation and maintenance of a unique competent immune synapse.
Published: 2022

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