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197 results on '"Immunité et cancer ( U932 )"'

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. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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

30. Radiotherapy or Autologous Stem-Cell Transplantation for Primary CNS Lymphoma in Patients Age 60 Years and Younger: Long-Term Results of the Randomized Phase II PRECIS Study

Author

Houillier, Caroline, Dureau, S, Taillandier, Luc, Houot, Roch, Chinot, O., Molucon-Chabrot, Cécile, Schmitt, Anna, Gressin, Rémy, Choquet, Sylvain, Damaj, Gandhi, Peyrade, Frédéric, Abraham, Julie, Delwail, V, Gyan, Emmanuel, Sanhes, Laurence, Cornillon, Jerome, Garidi, Reda, Delmer, Alain, Al Jijakli, Ahmad, Morel, Pierre, Waultier, Agathe, Paillassa, Jérôme, Chauchet, A, Gastinne, Thomas, Laadhari, Mouna, Plissonnier, Anne-Sophie, Feuvret, Loïc, Cassoux, Nathalie, Touitou, Valerie, Ricard, Jean-Damien, Hoang-Xuan, Khe, Soussain, Carole, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Curie [Paris], Centre Hospitalier Universitaire de Nancy (CHU Nancy), 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], Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Louise Michel [Clermont-Ferrand], CHU Clermont-Ferrand, Institut Bergonié [Bordeaux], UNICANCER, Centre Hospitalier Universitaire [Grenoble] (CHU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Amiens-Picardie, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), CHU Limoges, 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), Centre d’Investigation Clinique [Tours] CIC 1415 (CIC ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Saint Jean de Perpignan, Institut de Cancérologie Lucien Neuwirth, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre Hospitalier Universitaire de Reims (CHU Reims), Centre Hospitalier de Lens, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital d'instruction des Armées Percy, Service de Santé des Armées, Immunité et cancer (U932), and Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Adult, Cancer Research, Adolescent, Lymphoma, [SDV]Life Sciences [q-bio], Hematopoietic Stem Cell Transplantation, Middle Aged, Transplantation, Autologous, Combined Modality Therapy, Central Nervous System Neoplasms, Young Adult, Oncology, Antineoplastic Combined Chemotherapy Protocols, Humans, Neoplasm Recurrence, Local
Abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. We previously reported the results of a randomized phase II study in patients with newly diagnosed primary CNS lymphoma (age 18-60 years). Patients were treated with high-dose methotrexate-based induction chemotherapy followed by whole-brain radiotherapy (WBRT) or high-dose chemotherapy (thiotepa-busulfan-cyclophosphamide) with autologous stem-cell transplantation (ASCT). The median follow-up was 33 months. In this report, we provide long-term data (median follow-up, 8 years) regarding the outcomes and toxicities. Fifty-three and 44 patients received induction chemotherapy followed by WBRT or ASCT, respectively. Their 8-year event-free survival from random assignment was 67% and 39% in the ASCT and WBRT arms, respectively ( P = .03), with a significantly lower risk of relapse after ASCT (hazard ratio, 0.13; P < .001). One third of patients who relapsed after WBRT were alive after salvage treatment. Five and four patients died of ASCT and WBRT-related toxicities, respectively. The 8-year overall survival was 69% and 65% in the ASCT and WBRT arms, respectively (not significant). Balance (52% v 10%, P ≤ 0.001) and neurocognition (64% v 13%, P < .001) significantly deteriorated after WBRT compared with ASCT during the follow-up. This study shows that 40 Gy WBRT should be avoided in first-line treatment because of its neurotoxicity and suboptimal efficacy in reducing relapses while ASCT appears to be highly efficient in preventing relapses.

Published
2022

31. Dynamics of HIV-Containing Compartments in Macrophages Reveal Sequestration of Virions and Transient Surface Connections

Author

Jérémie Decalf, Raphael Gaudin, Stefano Berre, Mabel Jouve, François-Xavier Gobert, Bruna Cunha de Alencar, Michael Schindler, Philippe Benaroch, 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], Helmholtz Zentrum München = German Research Center for Environmental Health, Génétique et Biologie du Développement, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This study was supported by grants from « Ensemble contre le SIDA and ‘‘Agence Nationale de Recherche contre le SIDA’’ to PB and fellowships o BCdA and RG, respectively. SB was supported by a fellowship from the Institut Curie., Vougny, Marie-Christine, 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, Helmholtz-Zentrum München ( HZM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -INSTITUT CURIE-Centre National de la Recherche Scientifique ( CNRS ), Helmholtz-Zentrum München (HZM), and Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
Cytoplasm, Viral Diseases, Time Factors, viruses, lcsh:Medicine, Pathogenesis, Monocytes, Viral Packaging, Green fluorescent protein, Cell membrane, Immunodeficiency Viruses, Molecular Cell Biology, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Macrophage, lcsh:Science, Infectivity, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 0303 health sciences, Multidisciplinary, Viral Immune Evasion, Cellular Structures, Viral Persistence and Latency, 3. Good health, Cell biology, Host-Pathogen Interaction, Infectious Diseases, medicine.anatomical_structure, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Membranes and Sorting, Cellular Types, Intracellular, Research Article, Adult, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immune Cells, Immunology, Antigen-Presenting Cells, Biology, Models, Biological, Microbiology, [ SDV.MP.VIR ] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 03 medical and health sciences, Live cell imaging, Virology, Extracellular, medicine, Humans, Secretion, 030304 developmental biology, Blood Cells, 030306 microbiology, Macrophages, Cell Membrane, Host Cells, lcsh:R, Virion, Immunity, HIV, Viral Replication, Cell Compartmentation, Subcellular Organelles, HIV-1, lcsh:Q, Extracellular Space, Viral Transmission and Infection
Abstract

International audience; During HIV pathogenesis, infected macrophages behave as ‘‘viral reservoirs’’ that accumulate and retain virions withindedicated internal Virus-Containing Compartments (VCCs). The nature of VCCs remains ill characterized and controversial.Using wild-type HIV-1 and a replication-competent HIV-1 carrying GFP internal to the Gag precursor, we analyzed thebiogenesis and evolution of VCCs in primary human macrophages. VCCs appear roughly 14 hours after viral proteinsynthesis is detected, initially contain few motile viral particles, and then mature to fill up with virions that become packedand immobile. The amount of intracellular Gag, the proportion of dense VCCs, and the density of viral particles in theirlumen increased with time post-infection. In contrast, the secretion of virions, their infectivity and their transmission to Tcells decreased overtime, suggesting that HIV-infected macrophages tend to pack and retain newly formed virions intodense compartments. A minor proportion of VCCs remains connected to the plasma membrane overtime. Surprisingly, livecell imaging combined with correlative light and electron microscopy revealed that such connections can be transient,highlighting their dynamic nature. Together, our results shed light on the late phases of the HIV-1 cycle and reveal some ofits macrophage specific features

Published
2013

32. Risk of tumorigenicity in mesenchymal stromal cell-based therapies--bridging scientific observations and regulatory viewpoints

Author

Paula Salmikangas, Olivier Lantz, Marcel Kwa, Peter Ahnert, Arnaud Foussat, Sophie Lucas-Samuel, Lisbeth Barkholt, Karin Tarte, Romaldas Mačiulaitis, Christian K. Schneider, Gérard Tachdjian, Dirk Büscher, Luc Sensebé, Tiina Palomäki, Lucie Tosca, Veronika Jekerle, Willem E. Fibbe, Egbert Flory, Louise Bisset, Cell products working party (CPWP), European Medicines Agency, Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], GRI-CEL, Leiden University Medical Center (LUMC), TxCell, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Lithuanian university of health sciences, Institute of physiology and pharmacology, Danish health and medicines authority, STROMALab, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Modèles de Cellules Souches Malignes et Thérapeutiques, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Microenvironnement et cancer (MiCa), Université de Rennes 1 (UR1), 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 ), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Leipzig-Universität Leipzig, Universiteit Leiden, Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), 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 ), Cell products working party ( CPWP ), Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Toulouse III - Paul Sabatier ( UPS ), 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 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Microenvironnement et cancer ( MiCa ), Université de Rennes 1 ( UR1 ), 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 ), Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Etablissement Français du Sang-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)

Subjects
Cancer Research, Pathology, medicine.medical_specialty, Stromal cell, Carcinogenesis, Immunology, Cell Culture Techniques, Bone Marrow Cells, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, mesenchymal, Mesenchymal Stem Cell Transplantation, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Immunology and Allergy, Genetics (clinical), Cell Proliferation, 030304 developmental biology, 0303 health sciences, Transplantation, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, business.industry, Mesenchymal stem cell, Cell Differentiation, Mesenchymal Stem Cells, Cell Biology, cell, Viewpoints, 3. Good health, Adipose Tissue, Oncology, 030220 oncology & carcinogenesis, tumorigenicity, stromal, business
Abstract

International audience; In the past decade, the therapeutic value of mesenchymal stromal cells (MSCs) has been studied in various indications, thereby taking advantage of their immunosuppressive properties. Easy procurement from bone marrow, adipose tissue or other sources and conventional in vitro expansion culture have made their clinical use attractive. Bridging the gap between current scientific knowledge and regulatory prospects on the transformation potential and possible tumorigenicity of MSCs, the Cell Products Working Party and the Committee for Advanced Therapies organized a meeting with leading European experts in the field of MSCs. This meeting elucidated the risk of potential tumorigenicity related to MSC-based therapies from two angles: the scientific perspective and the regulatory point of view. The conclusions of this meeting, including the current regulatory thinking on quality, nonclinical and clinical aspects for MSCs, are presented in this review, leading to a clearer way forward for the development of such products.

Published
2013

33. Utilisation d'un anticorps monoclonal anti-Tn en immunothérapie des cancers

Author

Heitzmann-Daverton , Adèle, 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 René Descartes - Paris V, Sebastian Amigorena, 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
Monoclonal antibody, Immunoconjugué, Auristatine F, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Immunothérapie, Immunotherapy, Internalisation, Anticorps monoclonal, Saporine, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Internalization
Abstract

Pas de résumé en anglais; La transformation des cellules normales de l’organisme en un phénotype malin est souvent accompagnée de changements dans leur antigénicité. L’antigène Tn (GalNac-O-Ser/Thréo) est un antigène (Ag) glycopeptidique spécifique des tumeurs et exprimé à la membrane plasmique des cellules cancéreuses dans la majorité des carcinomes humains ainsi que dans certaines tumeurs hématologiques, tandis qu’il n’est pas détecté dans les cellules normales. Il représente donc une cible potentielle très intéressante pour l’immunothérapie passive par anticorps, car il n’est pas détectable dans les cellules normales, mais est démasqué dans environ 90% des cancers épithéliaux du fait d’une dérégulation des processus de glycosylation. Les anticorps monoclonaux (AcM) spécifiques d’antigènes exprimés à la membrane des cellules tumorales ont une efficacité prouvée dans le traitement de certains cancers. Ces AcM thérapeutiques sont particulièrement intéressants pour le traitement des cancers du fait de leur forte spécificité pour les cellules tumorales et de leur faible toxicité pour les cellules normales, contrairement aux chimiothérapies conventionnelles, mais leur mécanisme d’action est encore mal connu. L’AcM Chi-Tn est un anticorps chimérique homme/souris capable de se fixer de façon spécifique à l’antigène tumoral Tn, alors qu’il ne se fixe pas sur les cellules normales. Cet AcM pourrait donc être envisagé comme agent thérapeutique dans le traitement des cancers épithéliaux par immunothérapie passive.Nous nous sommes intéressés à l’AcM Chi-Tn non couplé en vue d’analyser son mécanisme d’action et d’évaluer son efficacité thérapeutique in vivo. Nous avons montré que l’AcM Chi-Tn seul ne possède pas d’effet toxique direct sur les lignées de cellules tumorales Tn-positives in vitro. Cependant, en présence de macrophages, cet AcM est capable d’induire la lyse de ces cellules par un mécanisme d’ADCC. In vivo, l’AcM Chi-Tn, associé à la cyclophosphamide, induit le rejet d'une tumeur du sein dans plus de 80% des souris. Cette inhibition de la croissance tumorale est abolie chez les souris déficientes pour la chaine associée aux récepteurs RFc activateurs, suggérant in vivo un mécanisme d’ADCC. Par l’étude microscopique du microenvironnement tumoral, nous avons observé que les cellules tumorales forment in vivo des synapses avec des macrophages, des neutrophiles, mais aussi des lymphocytes B. Des expériences de survie in vivo chez des souris déficientes pour différentes populations cellulaires montrent que les lymphocytes T semblent nécessaires à la protection des souris par Chi-Tn contre la tumeur. Ainsi, ces résultats confirment le rôle des effecteurs exprimant des RFc activateurs, mais aussi le rôle indispensable de la réponse immune adaptative pour assurer l'effet thérapeutique des AcM.Nous nous sommes également intéressés à l’utilisation potentielle de l’AcM Chi-Tn comme vecteur d’agents cytotoxiques. In vivo, dans un modèle de tumeurs solides chez la souris, des expériences de biodistribution montrent que l’AcM Chi-Tn est capable de cibler spécifiquement les zones tumorales, ce qui en fait un anticorps potentiellement utilisable comme vecteur de molécules toxiques. L’internalisation du complexe anticorps/antigène cible est un pré-requis nécessaire à l’utilisation de l’anticorps conjugué. Nous avons montré in vitro que l’AcM Chi-Tn est internalisé dans les endosomes précoces et de recyclage pendant un temps relativement long, faisant de cet AcM un bon candidat pour être couplé à des agents cytotoxiques. Durant ma thèse, nous avons couplé l’AcM Chi-Tn à la toxine saporine ou à la molécule cytotoxique auristatine F, et nous avons montré in vitro que ces conjugués sont cytotoxiques sur des lignées cellulaires Tn-positives.

Published
2013

34. Interactions cytokiniques dans le microenvironnement inflammatoire : analyse à large échelle de la réponse aux Interférons de Type I lors la de polarisation des Lymphocytes T auxiliaires

Author

Touzot, Maxime, 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 Sud - Paris XI, Vassili Soumelis, STAR, ABES, Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Biologie intégrative des cellules dendritiques et des cellules T chez l'homme, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5)

Subjects
[SDV.IMM] Life Sciences [q-bio]/Immunology, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Th, HIV, [SDV.IMM]Life Sciences [q-bio]/Immunology, Analyse à large échelle, Lymphocytes T auxiliaires, IFN, Cytokine, Large-scale analysis
Abstract

Type I IFN (IFN) are innate cytokines produced by host cells during viral infection. Ithas pleiotropic and sometimes opposing, protective or detrimental effects, on both innateand adaptive immunity that remain poorly understood. Parts of IFN response may be explain by intrinsic effect (cell-­‐specificity). My thesis was focused on the effect of the microenvironment, as present during T Helper cell differentiation, on IFN response. Using a systems level approach, we studied IFN responses during Four Human T Helper cell differentiation. We identified 1/ a conserved IFN-­‐induced transcriptional program comprising mostly antiviral genes 2/ a flexible IFN response, leading to a different pattern of chemokine and cytokine induction by IFN in distinct Th environments. Antiviral response was also flexible with a lesser protection to HIV-1 and HIV-2 infection in Th2 and Th17 contexts. Our in vitro results suggested that environmental control might shape the effects of IFN in different physiopathological contexts., Les interférons de Type I (IFN) sont des cytokines produites par les cellules en réponse à une infection virale. Les IFNs ont des effets pleïotropiques et parfois paradoxaux, protecteur ou néfaste pour l’immunité Innée ou adaptative. Certains facteurs intrinsèques (type cellulaire) peuvent expliquer une partie ces discordances. Mon travail de thèse s’est intéressé à l‘effet du microenvironnement cytokinique sur la réponse IFN. En utilisant des analyses à large échelle, nous avons étudié la réponse IFN dans 4 contextes de polarisation des lymphocytes T auxiliaires (Th). Nous avons identifié 1/ un programme de transcription conservé et 2/ une réponse IFN flexible, modulant spécifiquement les principales fonctions des Th (cytokines, chemokines) en fonction du contexte polarisant. La réponse antivirale apparait aussi flexible avec une moins bonne protection des Th2 et Th17 contre l’infection par HIV-1et HIV-2. Nos résultats suggèrent que l’environnement cytokinique contrôle en partie la réponse IFN et peut ainsi moduler cette dernière dans différents contextes physiopathologiques.

Published
2013

35. Kinesin KIFC1 actively transports bare double-stranded DNA

Author

Florent Dingli, Damarys Loew, Jordan Monnet, Maria Quanz, Paolo Pierobon, Francesca Farina, Giovanni Cappello, Cédric Delevoye, Marie Dutreix, Physico-Chimie-Curie (PCC), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Structure et compartimentation membranaire, Compartimentation et dynamique cellulaires (CDC), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), Spectrométrie de Masse et Protéomique [IBPS] (IBPS-SPM), Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Signalisation normale et pathologique de l'embryon aux thérapies innovantes des cancers, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), HAL UPMC, Gestionnaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Physico-Chimie-Curie ( PCC ), Centre National de la Recherche Scientifique ( CNRS ) -INSTITUT CURIE-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, Compartimentation et dynamique cellulaires ( CDC ), Centre National de la Recherche Scientifique ( CNRS ) -INSTITUT CURIE-Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ) -INSTITUT CURIE-Université Pierre et Marie Curie - Paris 6 ( UPMC ), Spectrométrie de Masse et Protéomique [IBPS] ( IBPS-SPM ), Institut de Biologie Paris Seine ( IBPS ), Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Signalisation normale et pathologique de l'embryon aux thérapies innovante des cancers, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -INSTITUT CURIE-Centre National de la Recherche Scientifique ( CNRS ), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Spectrométrie de Masse des Protéines, and Institut Curie [Paris]

Subjects
[PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], Biological Transport, Active, Kinesins, Genome Integrity, Repair and Replication, Biology, Microtubules, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Microtubule, Genetics, Molecular motor, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, Microscopy, Phase-Contrast, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Cytoskeleton, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, 0303 health sciences, [PHYS.PHYS.PHYS-BIO-PH] Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], DNA transport, Dyneins, DNA, Cell biology, Microscopy, Fluorescence, chemistry, Cytoplasm, 030220 oncology & carcinogenesis, Kinesin, Exogenous DNA, HeLa Cells
Abstract

International audience; During the past years, exogenous DNA molecules have been used in gene and molecular therapy. At present, it is not known how these DNA molecules reach the cell nucleus. We used an in cell single-molecule approach to observe the motion of exogenous short DNA molecules in the cytoplasm of eukaryotic cells. Our observations suggest an active transport of the DNA along the cytoskeleton filaments. We used an in vitro motility assay, in which the motion of single-DNA molecules along cytoskeleton filaments in cell extracts is monitored; we demonstrate that microtubule-associated motors are involved in this transport. Precipitation of DNA-bound proteins and mass spectrometry analyses reveal the preferential binding of the kinesin KIFC1 on DNA. Cell extract depletion of kinesin KIFC1 significantly decreases DNA motion, confirming the active implication of this molecular motor in the intracellular DNA transport.

Published
2013

36. Nef variants from non-pathogenic lentiviral strains inhibit iron uptake through an AP2-dependent inhibition of transferrin endocytosis

Author

Miriam Widder, Swantje Gundlach, François-Xavier Gobert, Anke Heigele, Herwig Koppensteiner, Marcos Vinícius Pereira Gondim, Philippe Benaroch, Michael Winkler, Michael Schindler, Kristin Höhne, Frank Kirchhoff, Institute of Virology, German Research Center for Environmental Health-Helmholtz-Zentrum München (HZM), Heinrich Pette Institute [Hamburg], Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Universitätsklinikum Ulm - University Hospital of Ulm, Infection Biology Unit, German Primate Center - Deutsches Primatenzentrum -- Leibniz Insitute for Primate Research -- [Göttingen, Allemagne] (GPC - DPZ), 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, Institute of Molecular Virology, and German Primate Center

Subjects
viruses, Endocytosis, Cofactor, 03 medical and health sciences, Protein structure, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Virology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Iron uptake, biology, 030306 microbiology, virus diseases, 3. Good health, Cell biology, [ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Infectious Diseases, Viral replication, chemistry, Transferrin, Poster Presentation, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, biology.protein, Antibody, 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 of whether modulation of intracellular iron can be linked to the pathogenicity of lentiviral infections. Here, we evaluated the effect on cellular iron uptake upon expression of the accessory protein Nef from divergent lentiviruses.

Published
2013

37. Inflammatory dendritic cells in mice and humans

Author

Elodie Segura, Sebastian Amigorena, Segura, Elodie, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Our work is supported by INSERM, European Research Council (2008-AdG n°233062 19 PhagoDC) and Ligue contre le Cancer, 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
MESH: Cell Differentiation, MESH: Inflammation, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Inflammation, Lymphocyte Activation, MESH: Monocytes, Monocytes, Mice, 03 medical and health sciences, 0302 clinical medicine, MESH : Mice, Animals, Humans, Immunology and Allergy, Medicine, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH: Animals, dendritic cells, MESH: Lymphocyte Activation, MESH: Mice, MESH : Lymphocyte Activation, 030304 developmental biology, 0303 health sciences, MESH : Inflammation, MESH: Humans, Follicular dendritic cells, MESH: Dendritic Cells, business.industry, MESH : Humans, Cell Differentiation, Phenotype, 3. Good health, Heterogeneous population, medicine.anatomical_structure, MESH : Monocytes, inflammation, MESH : Dendritic Cells, [SDV.IMM]Life Sciences [q-bio]/Immunology, Bone marrow, MESH : Animals, medicine.symptom, business, MESH : Cell Differentiation, 030215 immunology
Abstract

International audience; Dendritic cells (DCs) are a heterogeneous population of professional antigen-presenting cells. Several murine DC subsets have been identified that differ in their phenotype and functional properties. In the steady state, DC precursors originating from the bone marrow give rise to lymphoid-organ-resident DCs and to migratory tissue DCs. During inflammation, an additional DC subset has been described, so-called inflammatory DCs (infDCs), which differentiate from monocytes recruited to the site of inflammation. Here, we review recent work on the development and functions of murine infDCs. We also examine the criteria that define infDCs. Finally, we discuss the characterization of human infDCs and their potential role in inflammatory diseases.

Published
2013

38. TRAIL but not FasL and TNFα, regulates IL-33 expression in murine hepatocytes during acute hepatitis

Author

Muhammad Imran Arshad, Sabrina Nabti, Annie L'Helgoualc'h, Michel Rauch, Claire Piquet-Pellorce, Christian Trautwein, Frédéric Ezan, Michel Samson, Agnès Lehuen, Francisco Javier Cubero, Catherine Lucas-Clerc, Jean-Philippe Girard, Solène Patrat-Delon, Institut de recherche, santé, environnement et travail ( Irset ), Université d'Angers ( UA ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -École des Hautes Études en Santé Publique [EHESP] ( EHESP ) -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 ) -Université des Antilles ( UA ), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire de biochimie générale, Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Immunologie et génétique du diabète de type 1, génétique multifactorielle en endocrinologie pédiatrique ( U986 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Medical Department III, University Hospital Aachen, Institut de pharmacologie et de biologie structurale ( IPBS ), Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie et génétique du diabète de type 1, génétique multifactorielle en endocrinologie pédiatrique (U986), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH : RNA, Messenger, medicine.medical_treatment, Gene Expression, Galactosamine, MESH : Hepatocytes, Hepatitis, Animal, MESH : Fas Ligand Protein, Fas ligand, MESH: Antibodies, Monoclonal, TNF-Related Apoptosis-Inducing Ligand, MESH: Hepatocytes, MESH : TNF-Related Apoptosis-Inducing Ligand, Antibodies, Monoclonal, Murine-Derived, Mice, 0302 clinical medicine, MESH : Receptors, Tumor Necrosis Factor, Type I, MESH: Receptors, Tumor Necrosis Factor, Type II, Concanavalin A, MESH: Animals, MESH : Acute Lung Injury, MESH: Galactosamine, MESH : Concanavalin A, Liver injury, MESH: Receptors, Tumor Necrosis Factor, Type I, MESH : Tumor Necrosis Factor-alpha, 0303 health sciences, biology, MESH: Hepatitis, Animal, Antibodies, Monoclonal, Interleukin, MESH : Receptors, Tumor Necrosis Factor, Type II, Natural killer T cell, 3. Good health, Cytokine, Receptors, Tumor Necrosis Factor, Type I, 030220 oncology & carcinogenesis, MESH : Antibodies, Monoclonal, Tumor necrosis factor alpha, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: TNF-Related Apoptosis-Inducing Ligand, Fas Ligand Protein, MESH: Gene Expression, MESH: Interleukins, Acute Lung Injury, Primary Cell Culture, chemical and pharmacologic phenomena, MESH: Concanavalin A, MESH: Primary Cell Culture, 03 medical and health sciences, MESH : Mice, medicine, Animals, Receptors, Tumor Necrosis Factor, Type II, RNA, Messenger, MESH : Perforin, MESH : Primary Cell Culture, MESH: Mice, 030304 developmental biology, MESH: RNA, Messenger, Hepatitis, Hepatology, MESH : Galactosamine, Perforin, Tumor Necrosis Factor-alpha, Interleukins, MESH: Acute Lung Injury, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Interleukin-33, medicine.disease, MESH : Natural Killer T-Cells, MESH: Fas Ligand Protein, MESH: Perforin, MESH : Gene Expression, MESH: Natural Killer T-Cells, MESH: Tumor Necrosis Factor-alpha, Immunology, Hepatocytes, biology.protein, Cancer research, Natural Killer T-Cells, MESH : Animals, MESH : Interleukins, MESH : Hepatitis, Animal
Abstract

International audience; UNLABELLED: Interleukin (IL)-33, a member of the IL-1 cytokine family, positively correlates with acute hepatitis and chronic liver failure in mice and humans. IL-33 is expressed in hepatocytes and is regulated by natural killer T (NKT) cells during concanavalin A (ConA)-induced acute liver injury. Here, we investigated the molecular mechanisms underlying the expression of IL-33 during acute hepatitis. The expression of IL-33 and its regulation by death receptor pathways was investigated after the induction of ConA-acute hepatitis in wildtype (WT), perforin(-/-) , tumor necrosis factor related apoptosis inducing ligand (TRAIL)(-/-) , and NKT cell-deficient (CD1d(-/-) ) mice. In addition, we used a model of acute liver injury by administering Jo2/Fas-antibody or D-galactosamine-tumor necrosis factor alpha (TNFα) in WT mice. Finally, the effect of TRAIL on IL-33 expression was assessed in primary cultured murine hepatocytes. We show that IL-33 expression in hepatocytes is partially controlled by perforin during acute liver injury, but not by TNFα or Fas ligand (FasL). Interestingly, the expression of IL-33 in hepatocytes is blocked during ConA-acute hepatitis in TRAIL-deficient mice compared to WT mice. In contrast, administration of recombinant murine TRAIL associated with ConA-priming in CD1d-deficient mice or in vitro stimulation of murine hepatocytes by TRAIL but not by TNFα or Jo2 induced IL-33 expression in hepatocytes. The IL-33-deficient mice exhibited more severe ConA liver injury than WT controls, suggesting a protective effect of IL-33 in ConA-hepatitis. CONCLUSION: The expression of IL-33 during acute hepatitis is dependent on TRAIL, but not on FasL or TNFα.

Published
2012

39. Critical role for the kinesin KIF3A in the HIV life cycle in primary human macrophages

Author

Aditi Varthaman, Michael Schindler, Emmanuel Le Bouder, Mabel Jouve, Raphael Gaudin, Stefano Berre, Bruna Cunha de Alencar, François-Xavier Gobert, Philippe Benaroch, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institute of Virology, Helmholtz Zentrum Munich, German Research Center for Environmental Health, Helmholtz-Zentrum München (HZM), Agence Nationale de Recherche contre le SIDA (ANRS), Ensemble contre le SIDA (Sidaction), Curie Institute, Fondation pour la Recherche Médicale, Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Curie, Institut Jacques Monod ( IJM ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Helmholtz-Zentrum München ( HZM ), and Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Blotting, Western, Human immunodeficiency virus (HIV), Kinesins, HIV Infections, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, medicine.disease_cause, Microtubules, Article, 03 medical and health sciences, 0302 clinical medicine, Microtubule, Molecular motor, medicine, Humans, Gene silencing, KIF3A, [ SDV.BDD ] Life Sciences [q-bio]/Development Biology, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Research Articles, Cells, Cultured, 030304 developmental biology, 0303 health sciences, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, Macrophages, Virion, virus diseases, HIV, Cell Biology, Virus Release, 3. Good health, Cell biology, Blot, Kinesin, 030217 neurology & neurosurgery
Abstract

KIF3A is important for the intracellular transport of HIV-containing compartments and HIV release from infected macrophages., Macrophages are long-lived target cells for HIV infection and are considered viral reservoirs. HIV assembly in macrophages occurs in virus-containing compartments (VCCs) in which virions accumulate and are stored. The regulation of the trafficking and release of these VCCs remains unknown. Using high resolution light and electron microscopy of HIV-1–infected primary human macrophages, we show that the spatial distribution of VCCs depended on the microtubule network and that VCC-limiting membrane was closely associated with KIF3A+ microtubules. Silencing KIF3A strongly decreased virus release from HIV-1–infected macrophages, leading to VCC accumulation intracellularly. Time-lapse microscopy further suggested that VCCs and associated KIF3A move together along microtubules. Importantly, KIF3A does not play a role in HIV release from T cells that do not possess VCCs. These results reveal that HIV-1 requires the molecular motor KIF3 to complete its cycle in primary macrophages. Targeting this step may lead to novel strategies to eliminate this viral reservoir.

Published
2012

40. Rôle des protéines Rab27 dans la sécrétion des exosomes : implication dans l’étude des réponses immunitaires tumorales

Author

Bobrie, Angélique, Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université René Descartes - Paris V, Clotilde Théry, Immunité et cancer (U932), and Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Protéines Rab27, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Immunology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Pas de résumé en anglais; Pas de résumé en français

Published
2012

41. Characterization of resident and migratory dendritic cells in human lymph nodes

Author

Xavier Sastre-Garau, Elodie Segura, Marie-Hélène Donnadieu, Sebastian Amigorena, Jenny Valladeau-Guilemond, Vassili Soumelis, Immunité et cancer (U932), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5), Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de Biologie des Tumeurs, Institut Curie, 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 de Lyon ( 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 ) -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 ), INSTITUT CURIE, 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 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)-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), Institut Curie [Paris], Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
MESH: Antigens, CD1, Lipopolysaccharide Receptors, MESH : Receptors, Cell Surface, MESH: Lymph Nodes, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Antigens, CD1, 0302 clinical medicine, Cell Movement, MESH : Lectins, C-Type, Immunology and Allergy, MESH : Cell Movement, MESH: Cell Movement, MESH : Lymph Nodes, MESH : Mannose-Binding Lectins, Skin, MESH: Receptors, Cell Surface, 0303 health sciences, integumentary system, MESH: Dendritic Cells, MESH: Antigens, CD14, Cell Polarity, hemic and immune systems, 3. Good health, medicine.anatomical_structure, Lymph, MESH: Cell Polarity, MESH : Cell Polarity, Mannose Receptor, T cell, Immunology, Spleen, Receptors, Cell Surface, chemical and pharmacologic phenomena, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, Immune system, Th2 Cells, Antigen, MESH: Skin, MESH: Th2 Cells, MESH: Mannose-Binding Lectins, medicine, MESH : Skin, Humans, Lectins, C-Type, 030304 developmental biology, MESH: Humans, MESH : Humans, Brief Definitive Report, Dendritic Cells, In vitro, MESH : Th2 Cells, MESH : Antigens, CD14, Mannose-Binding Lectins, MESH : Antigens, CD1, Tonsil, MESH : Dendritic Cells, Lymph Nodes, CD8, MESH: Lectins, C-Type, 030215 immunology
Abstract

Human skin-draining lymph nodes contain functionally distinct subsets of resident and migratory dendritic cells., Dendritic cells (DCs) initiate adaptive immune responses in lymph nodes (LNs). In mice, LN DCs can be divided into resident and tissue-derived populations, the latter of which migrate from the peripheral tissues. In humans, different subsets of DCs have been identified in the blood, spleen, and skin, but less is known about populations of resident and migratory tissue-derived DCs in LNs. We have analyzed DCs in human LNs and identified two populations of resident DCs that are present in all LNs analyzed, as well as in the spleen and tonsil, and correspond to the two known blood DC subtypes. We also identify three main populations of skin-derived migratory DCs that are present only in skin-draining LNs and correspond to the DC subsets found in the skin. Resident DCs subsets induce both Th1 and Th2 cytokines in naive allogeneic T lymphocytes, whereas the corresponding blood subsets failed to induce efficient Th2 polarization. LN-resident DCs also cross-present antigen without in vitro activation, whereas blood DCs fail to do so. Among migratory DCs, one subset was poor at both CD4+ and CD8+ T cell activation, whereas the other subsets induced only Th2 polarization. We conclude that in humans, skin-draining LNs host both resident and migratory DC subsets with distinct functional abilities.

Published
2012

42. Sec22b regulates phagosomal maturation and antigen crosspresentation by dendritic cells

Author

Mabel Jouve, Catarina Moita, Jost Enninga, Ariel Savina, Geraldine Visentin, Nicolas Blanchard, Sebastian Amigorena, Luis F. Moita, Ignacio Cebrian, Alexandre Bobard, 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 Physiopathologie Toulouse Purpan (CPTP), 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), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Dynamique des Interactions Hôte-Pathogène - Dynamics of Host-Pathogen Interactions, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Cell Biology of the Immune System Unit, Universidade de Lisboa = University of Lisbon (ULISBOA)-Faculdade de Medicina-Instituto de Medicina Molecular, Institut Curie,Institut National de la Santé et de la Recherche Médicale (INSERM), ARC (Association de la Recherche contre le Cancer, N° SFI20101201629), Ligue National de Lutte contre le Cancer (Ligue labélisée 2007-2010 and 2011-2013), European Research Council (PhagoDC n°233062), Agence National de Recherche (ANR MIME APAT), Bettencourt-Schueller Foundation (FBS), Human Frontier Science Program Organization, Curie Institute PhD Scholarship program, Fundação Luso-Americana para o Desenvolvimento and Fundação para a Ciência e a Tecnologia (PTDC/SAU-IMU/110303/2009, PTDC/SAU-MII/100780/2008, and PIC/IC/82991/2007), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Dynamique des Interactions Hôte-Pathogène, Institut Pasteur [Paris], Universidade de Lisboa (ULISBOA)-Faculdade de Medicina-Instituto de Medicina Molecular, Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Curie, Centre de Physiopathologie de Toulouse Purpan ( CPTP ), Université Toulouse III - Paul Sabatier ( UPS ), 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 Jacques Monod ( IJM ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Universidade de Lisboa ( ULISBOA ) -Faculdade de Medicina-Instituto de Medicina Molecular, 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), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
Phagocytosis, Antigen presentation, Vacuole, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Cross Reactions, Endocytosis, General Biochemistry, Genetics and Molecular Biology, R-SNARE Proteins, 03 medical and health sciences, Mice, 0302 clinical medicine, Antigen, Phagosomes, MHC class I, Escherichia coli, Animals, Escherichia coli Infections, 030304 developmental biology, Phagosome, 0303 health sciences, Antigen Presentation, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, Biochemistry, Genetics and Molecular Biology(all), Dendritic Cells, Cell biology, Mice, Inbred C57BL, 030220 oncology & carcinogenesis, biology.protein, Toxoplasma, CD8, Toxoplasmosis
Abstract

International audience; Antigen (Ag) crosspresentation by dendritic cells (DCs) involves the presentation of internalized Ags on MHC class I molecules to initiate CD8+ T cell-mediated immunity in response to certain pathogens and tumor cells. Here, we identify the SNARE Sec22b as a specific regulator of Ag crosspresentation. Sec22b localizes to the ER-Golgi intermediate compartment (ERGIC) and pairs to the plasma membrane SNARE syntaxin 4, which is present in phagosomes (Phgs). Depletion of Sec22b inhibits the recruitment of ER-resident proteins to Phgs and to the vacuole containing the Toxoplasma gondii parasite. In Sec22b-deficient DCs, crosspresentation is compromised after Ag phagocytosis or endocytosis and after invasion by T. gondii. Sec22b silencing inhibited Ag export to the cytosol and increased phagosomal degradation by accelerating lysosomal recruitment. Our findings provide insight into an intracellular traffic pathway required for crosspresentation and show that Sec22b-dependent recruitment of ER proteins to Phgs critically influences phagosomal functions in DCs.

Published
2011

43. Semen clusterin is a novel DC-SIGN ligand

Author

Wolfgang Faigle, Emilio L. Malchiodi, Fernando Arenzana-Seisdedos, Franck Fieschi, Jean-Claude Michalski, Hugues Lortat-Jacob, Michel Thépaut, Sebastian Amigorena, Juan Sabatté, Ana Ceballos, Willy Morelle, Federico Remes Lenicov, Christian Rodriguez Rodrigues, Jorge Geffner, Marisa M. Fernández, Institut de biologie structurale ( IBS - UMR 5075 ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Université Joseph Fourier - Grenoble 1 ( UJF ), Institut Curie, Collège de France ( CDF ), Collège de France ( CdF ), National Reference center for AIDS, Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 ( UGSF ), Institut National de la Recherche Agronomique ( INRA ) -Université de Lille-Centre National de la Recherche Scientifique ( CNRS ), Departamento de Matemáticas, Universidad del Pais Vasco / Euskal Herriko Unibertsitatea ( UPV/EHU ), Pathogénie Virale, Institut Pasteur [Paris]-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, Institut de biologie structurale (IBS - UMR 5075), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), 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)-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)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), Collège de France (CDF), Collège de France (CdF), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Universidad del Pais Vasco / Euskal Herriko Unibertsitatea [Espagne] (UPV/EHU), Institut Pasteur [Paris]-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 de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris], Laboratoire de Spectrométrie de Masse Protéomique, Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), 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)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5)

Subjects
Male, Glycosylation, MESH : Receptors, Cell Surface, Mannose, Plasma protein binding, Ligands, MESH: Recombinant Proteins, MESH: HIV-1, chemistry.chemical_compound, 0302 clinical medicine, MESH: Ligands, MESH : Lectins, C-Type, Immunology and Allergy, Receptor, MESH: Receptors, Cell Surface, 0303 health sciences, MESH : Ligands, MESH: Middle Aged, MESH: Dendritic Cells, MESH : Glycosylation, MESH : Protein Binding, Middle Aged, MESH : Adult, MESH: Glycosylation, Recombinant Proteins, 3. Good health, Cell biology, MESH : Antiviral Agents, DC-SIGN, MESH: Mannose, 030220 oncology & carcinogenesis, MESH: Cell Adhesion Molecules, MESH : HIV-1, Protein Binding, MESH : Fucose, Adult, MESH: Antiviral Agents, Glycan, MESH : Recombinant Proteins, MESH : Male, Immunology, Semen, Receptors, Cell Surface, Biology, MESH : Semen, Antiviral Agents, MESH : Cell Adhesion Molecules, MESH : Clusterin, 03 medical and health sciences, Humans, MESH: Protein Binding, Lectins, C-Type, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : Middle Aged, MESH: Fucose, MESH: Semen, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Fucose, MESH: Humans, MESH : Mannose, Clusterin, MESH : Humans, MESH: Adult, Dendritic Cells, Molecular biology, MESH: Male, eye diseases, chemistry, MESH: Clusterin, MESH : Dendritic Cells, biology.protein, HIV-1, sense organs, Cell Adhesion Molecules, MESH: Lectins, C-Type
Abstract

The C-type lectin receptor dendritic cell-specific ICAM-3–grabbing nonintegrin (DC-SIGN) is an important player in the recognition of pathogens by dendritic cells. A plethora of pathogens including viruses, bacteria, parasites, and fungi are recognized by DC-SIGN through both mannose and fucose-containing glycans expressed on the pathogen surface. In this study, we identified semen clusterin as a novel DC-SIGN ligand. Semen clusterin, but not serum clusterin, expresses an extreme abundance of fucose-containing blood-type Ags such as Lex and Ley, which are both excellent DC-SIGN ligands. These motifs enable semen clusterin to bind DC-SIGN with very high affinity (Kd 76 nM) and abrogate the binding of HIV-1 to DC-SIGN. Depletion of clusterin from semen samples, however, did not completely prevent the ability of semen to inhibit the capture of HIV-1 by DC-SIGN, supporting that besides clusterin, semen contains other DC-SIGN ligands. Further studies are needed to characterize these ligands and define their contribution to the DC-SIGN–blocking activity mediated by semen. Clusterin is an enigmatic protein involved in a variety of physiologic and pathologic processes including inflammation, atherosclerosis, and cancer. Our results uncover an unexpected heterogeneity in the glycosylation pattern of clusterin and suggest that the expression of high concentrations of fucose-containing glycans enables semen clusterin to display a unique set of biological functions that might affect the early course of sexually transmitted infectious diseases.

Published
2011

44. Antibody-dependent cell cytotoxicity synapses form in mice during tumor-specific antibody immunotherapy

Author

André Nicolas, Otto Pritsch, Sophie Viel, Sebastian Amigorena, Pablo Oppezzo, Adele Heitzmann, Xavier Sastre-Garau, Pascale Hubert, Eduardo Osinaga, 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], Département de Biologie des Tumeurs, Institut Pasteur de Montevideo, Réseau International des Instituts Pasteur (RIIP), Departamento de inmunobiologia, Facultad de Medicina- Universidad de la República [Montevideo] (UCUR), This work was financially supported by the Institut National de la Sante et de la Recherche Medicale, the Association pour la Recherche sur le Cancer (ARC), the Institut Curie, the EC grant ENCITE, Health-F5-2008-201842, the Institut National du Cancer (INCa)., Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5), Institut Curie, 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, Réseau International des Instituts Pasteur ( RIIP ) -Institut Pasteur de Montevideo, and Universidad de la República-Facultad de Medicina

Subjects
Immunological Synapses, Antibodies, Neoplasm, medicine.medical_treatment, MESH : Breast Neoplasms, MESH: Neutrophils, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Antibodies, Monoclonal, MESH : Neutrophils, Mice, MESH : Antibody-Dependent Cell Cytotoxicity, 0302 clinical medicine, Antibody Specificity, MESH: Animals, MESH : Tumor Microenvironment, MESH : Receptors, IgG, MESH : Macrophages, Ovarian Neoplasms, 0303 health sciences, MESH: Antigens, Tumor-Associated, Carbohydrate, Antibodies, Monoclonal, MESH: Cystadenocarcinoma, Serous, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Monoclonal, MESH: Immunization, Passive, Antibody, MESH: Receptors, IgG, Monoclonal antibody, MESH : Antigens, Tumor-Associated, Carbohydrate, 03 medical and health sciences, Antigen, In vivo, Humans, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Antineoplastic Agents, Alkylating, Cyclophosphamide, MESH: Humans, Macrophages, MESH : Humans, Antibody-Dependent Cell Cytotoxicity, Immunization, Passive, MESH: Cyclophosphamide, Immunotherapy, Cystadenocarcinoma, Serous, MESH: Antibodies, Monoclonal, Humanized, MESH: Female, Cancer Research, MESH: Combined Modality Therapy, MESH : Immunization, Passive, Neutrophils, MESH: Antineoplastic Agents, Alkylating, MESH: Tumor Microenvironment, Tumor Microenvironment, MESH : Female, MESH : Cyclophosphamide, MESH : Immunological Synapses, MESH : Antibody Specificity, MESH : Cystadenocarcinoma, Serous, Antibody-dependent cell-mediated cytotoxicity, Mice, Inbred BALB C, biology, Combined Modality Therapy, MESH: Ovarian Neoplasms, MESH : Antibodies, Monoclonal, Female, MESH : Antibodies, Neoplasm, MESH : Mammary Neoplasms, Experimental, MESH: Cell Line, Tumor, medicine.drug_class, MESH : Antineoplastic Agents, Alkylating, MESH: Mammary Neoplasms, Experimental, MESH: Mice, Inbred BALB C, Breast Neoplasms, chemical and pharmacologic phenomena, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antibodies, Monoclonal, Humanized, MESH : Antibodies, Monoclonal, Humanized, Cell Line, Tumor, MESH: Immunological Synapses, MESH : Mice, medicine, MESH: Antibody-Dependent Cell Cytotoxicity, Animals, Antigens, Tumor-Associated, Carbohydrate, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Antibody Specificity, MESH: Mice, MESH : Mice, Inbred BALB C, 030304 developmental biology, Innate immune system, MESH : Ovarian Neoplasms, MESH : Cell Line, Tumor, Receptors, IgG, Mammary Neoplasms, Experimental, MESH: Macrophages, Trastuzumab, Molecular biology, MESH: Antibodies, Neoplasm, biology.protein, MESH : Animals, MESH : Combined Modality Therapy, MESH: Breast Neoplasms
Abstract

Antibody-dependent cell cytotoxicity (ADCC) plays a critical role in monoclonal antibody (mAb)-mediated cancer therapy. ADCC, however, has not been directly shown in vivo but inferred from the requirement for IgG Fc receptors (FcγR) in tumor rejection in mice. Here, we investigated the mechanism of action of a Tn antigen-specific chimeric mAb (Chi-Tn), which binds selectively to a wide variety of carcinomas, but not to normal tissues, in both humans and mice. Chi-Tn mAb showed no direct toxicity against carcinomas cell lines in vitro but induced the rejection of a murine breast tumor in 80% to 100% of immunocompetent mice, when associated with cyclophosphamide. Tumor rejection was abolished in Fc receptors–associated γ chain (FcR-γ)–deficient mice, suggesting a role for ADCC. Indeed, tumor cells formed stable conjugates in vivo with FcR-γ chain-expressing macrophages and neutrophils in Chi-Tn mAb-treated but not in control mAb-treated mice. The contact zone between tumor cells and ADCC effectors accumulated actin, FcγR and phospho-tyrosines. The in vivo formed ADCC synapses were organized in multifocal supra-molecular activation clusters. These results show that in vivo ADCC mediated by macrophages and neutrophils during tumor rejection by Chi-Tn mAb involves a novel type of multifocal immune synapse between effectors of innate immunity and tumor cells. Cancer Res; 71(15); 5134–43. ©2011 AACR.

Published
2011

45. High levels of antibodies against merkel cell polyomavirus identify a subset of patients with merkel cell carcinoma with better clinical outcome

Author

Gérard Lorette, Eve Maubec, Agnès Carlotti, Annabel Maruani, Marie-Françoise Avril, Maxime Fleury, Raphaël Cazal, Serge Guyétant, Mauro Tognon, Flore Rozenberg, Françoise Arnold, Antoine Touzé, Emmanuelle Le Bidre, François Aubin, Pierre Coursaget, Hélène Laude, Laboratoire Analyse, Géométrie et Applications (LAGA), Université Paris 8 Vincennes-Saint-Denis (UP8)-Centre National de la Recherche Scientifique (CNRS)-Institut Galilée-Université Paris 13 (UP13), 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 dermatologie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Hôpital Saint-Jacques-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de Dermatologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de Virologie, Hôpital Saint-Vincent de Paul, Laboratoire Analyse, Géométrie et Applications ( LAGA ), Université Paris 8 Vincennes-Saint-Denis ( UP8 ) -Université Paris 13 ( UP13 ) -Université Sorbonne Paris Cité ( USPC ) -Institut Galilée-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 Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Saint-Jacques-Université de Franche-Comté ( UFC ), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC ( CEF2P / CARCINO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ), Service de Dermatologie, Hôpital Cochin, AP-HP, Paris, Université Paris 8 Vincennes-Saint-Denis (UP8)-Université Paris 13 (UP13)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Saint-Jacques-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) ( CEF2P / CARCINO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté [COMUE] ( UBFC ) -Université de Franche-Comté ( UFC ), and Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP]

Subjects
Pathology, MESH: Chi-Square Distribution, MESH: Lymphatic Metastasis, MESH: Polyomavirus, MESH : Aged, MESH : Prospective Studies, MESH: Risk Assessment, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Merkel cell carcinoma, 0302 clinical medicine, MESH: Up-Regulation, MESH : Neoplasm Staging, MESH : Up-Regulation, MESH: Capsid Proteins, 0303 health sciences, MESH: Middle Aged, Antibody titer, food and beverages, MESH : Lymphatic Metastasis, MESH : Enzyme-Linked Immunosorbent Assay, MESH: Case-Control Studies, MESH : Polyomavirus, 3. Good health, Oncology, 030220 oncology & carcinogenesis, MESH: RNA, Viral, VIRUS, Antibody, MESH : Case-Control Studies, medicine.medical_specialty, MESH: Prognosis, 03 medical and health sciences, MESH : Middle Aged, MESH : Predictive Value of Tests, MESH : Aged, 80 and over, MESH: Kaplan-Meier Estimate, MESH: Humans, MESH : Chi-Square Distribution, MESH : Humans, MESH: Adult, MESH : Proportional Hazards Models, medicine.disease, MESH: Tumor Markers, Biological, MESH: Disease-Free Survival, MESH: Female, SKIN, MESH: Antibodies, Viral, Cancer Research, MESH : Capsid Proteins, Merkel cell polyomavirus, Human skin, antibody, immune system, outcome, MESH: Proportional Hazards Models, MESH: Aged, 80 and over, MESH: Risk Factors, MESH : Tumor Markers, Biological, INFECTION, EPIDEMIOLOGY, MESH : Female, MESH : Risk Assessment, MESH : Carcinoma, Merkel Cell, MESH: Aged, MESH : Prognosis, biology, MESH: Enzyme-Linked Immunosorbent Assay, MESH: Neoplasm Staging, MESH : Adult, MESH : Risk Factors, MESH: Predictive Value of Tests, ETIOLOGY, MESH : Disease-Free Survival, MESH : Time Factors, circulatory and respiratory physiology, MESH : Antibodies, Viral, EXPRESSION, TISSUES, MESH : Male, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH : Kaplan-Meier Estimate, medicine, MESH : RNA, Viral, MESH : France, 030304 developmental biology, Insect cell, business.industry, MESH: Skin Neoplasms, MESH : Skin Neoplasms, MESH: Time Factors, Cancer, MESH: Carcinoma, Merkel Cell, biology.organism_classification, MESH: Male, MESH: Prospective Studies, MESH: France, Geometric mean titer, MCV, biology.protein, business
Abstract

Purpose A new human polyomavirus, Merkel cell polyomavirus (MCV), was identified in 2008 in tumor tissue of patients with Merkel cell carcinoma (MCC), a relatively rare human skin cancer. In this study, we investigated patients with MCC and controls for the presence of antibodies against MCV and their association with clinical characteristics. Patients and Methods Antibodies against MCV were investigated by enzyme-linked immunosorbent assay in 68 patients with MCC and 82 controls using VP1 virus-like particles produced in insect cells. Results Antibodies against MCV were detected in all patients with MCC and in 85% of controls. However, high antibody titers (> 10,000) were rarely observed in controls (7.3%) and they were detected in 64.7% of patients with MCC (P < .001) in contrast to the absence of VP1 expression in tumor samples. In addition, the geometric mean titer of anti-MCV in patients with MCC was around 14 times higher than that observed in MCV-positive controls (P < .001) and was not correlated with tumor viral load. High antibody titers were not found to be associated with any subject or tumor characteristics, but better progression-free survival was observed in patients with high antibody titers (hazard ratio, 4.6; 95% CI, 1.7 to 12.2; P = .002). Conclusion High titers of MCV antibodies in a much higher proportion of patients with MCC than in controls confirmed the association between MCV infection and MCC. The findings also indicated that a better progression-free survival occurred in patients with high MCV antibody titers and suggested that there are at least two distinct etiologic causes of MCC.

Published
2011

46. Viral infection prevents diabetes by inducing regulatory T cells through NKT cell-plasmacytoid dendritic cell interplay

Author

Agnès Lehuen, Roberto Mallone, Marc Dalod, Lucie Beaudoin, Julien Diana, Anna Tafuri, Vedran Brezar, Christian Boitard, Andrew L. Mellor, Matthias von Herrath, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), 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), Medical College of Georgia, Immunotherapy Center, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), La Jolla Institute for Immunology [La Jolla, CA, États-Unis], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), CHU Cochin [AP-HP], Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), La Jolla Institute for Allergy and Immunology (LIA), La Jolla Institute for Allergy & Immunology, Université Paris Descartes - Paris 5 ( UPD5 ), 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 ), Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), and La Jolla Institute for Allergy and Immunology ( LIA )

Subjects
MESH: Interleukin-10, endocrine system diseases, Programmed Cell Death 1 Receptor, MESH: Membrane Glycoproteins, MESH : Membrane Glycoproteins, MESH: Lymph Nodes, Cell Communication, CD8-Positive T-Lymphocytes, Lymphocyte Activation, T-Lymphocytes, Regulatory, B7-H1 Antigen, MESH : Diabetes Mellitus, Type 1, MESH : T-Lymphocytes, Regulatory, Interleukin 21, Mice, 0302 clinical medicine, Transforming Growth Factor beta, immune system diseases, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Immunology and Allergy, Cytotoxic T cell, MESH: Animals, IL-2 receptor, MESH : Antigens, CD80, MESH : Lymph Nodes, 0303 health sciences, Membrane Glycoproteins, MESH: Dendritic Cells, MESH : Peptides, MESH: Peptides, FOXP3, hemic and immune systems, MESH : CD8-Positive T-Lymphocytes, Natural killer T cell, MESH: CD8-Positive T-Lymphocytes, 3. Good health, Interleukin-10, MESH: Virus Diseases, medicine.anatomical_structure, Virus Diseases, Antigens, Surface, B7-1 Antigen, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Diabetes Mellitus, Type 1, MESH : Apoptosis Regulatory Proteins, MESH : Antigens, Surface, endocrine system, MESH : Cell Communication, MESH: Antigens, Surface, T cell, Immunology, macromolecular substances, Biology, Article, 03 medical and health sciences, Islets of Langerhans, MESH: Antigens, CD80, MESH : Interleukin-10, MESH : Mice, MESH: Cell Communication, medicine, Animals, MESH : Islets of Langerhans, Antigen-presenting cell, MESH: Lymphocyte Activation, MESH: Mice, MESH : Lymphocyte Activation, MESH: Transforming Growth Factor beta, 030304 developmental biology, MESH: Apoptosis Regulatory Proteins, MESH: T-Lymphocytes, Regulatory, MESH: Islets of Langerhans, Dendritic cell, Dendritic Cells, MESH : Virus Diseases, MESH : Natural Killer T-Cells, MESH : Transforming Growth Factor beta, Diabetes Mellitus, Type 1, MESH: Natural Killer T-Cells, MESH : Dendritic Cells, Natural Killer T-Cells, MESH : Animals, Lymph Nodes, Apoptosis Regulatory Proteins, Peptides, 030215 immunology
Abstract

iNKT cell and pDC cross talk prevents type 1 diabetes by inducing T reg cells in the pancreatic lymph node during viral infection., Type 1 diabetes (T1D) is an autoimmune disease resulting from T cell–mediated destruction of insulin-producing β cells, and viral infections can prevent the onset of disease. Invariant natural killer T cells (iNKT cells) exert a regulatory role in T1D by inhibiting autoimmune T cell responses. As iNKT cell–plasmacytoid dendritic cell (pDC) cooperation controls viral replication in the pancreatic islets, we investigated whether this cellular cross talk could interfere with T1D development during viral infection. Using both virus-induced and spontaneous mouse models of T1D, we show that upon viral infection, iNKT cells induce TGF-β–producing pDCs in the pancreatic lymph nodes (LNs). These tolerogenic pDCs convert naive anti-islet T cells into Foxp3+ CD4+ regulatory T cells (T reg cells) in pancreatic LNs. T reg cells are then recruited into the pancreatic islets where they produce TGF-β, which dampens the activity of viral- and islet-specific CD8+ T cells, thereby preventing T1D development in both T1D models. These findings reveal a crucial cooperation between iNKT cells, pDCs, and T reg cells for prevention of T1D by viral infection.

Published
2011

47. Residual HIV-1 DNA Flap-independent nuclear import of cPPT/CTS double mutant viruses does not support spreading infection

Author

Juliette Fernandez, Candela Iglesias, Francesca Di Nunzio, Nathalie J. Arhel, Mathieu Ringeard, Pierre Charneau, Philippe Souque, Raphael Gaudin, Centro de Investigacion en Enfermedades Infecciosas, Virologie moléculaire et vaccinologie, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -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]-Centre National de la Recherche Scientifique (CNRS), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), 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 Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and BMC, Ed.

Subjects
lcsh:Immunologic diseases. Allergy, Molecular Sequence Data, Active Transport, Cell Nucleus, HIV Infections, Biology, Virus Replication, medicine.disease_cause, Virus, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Virology, medicine, Humans, 030304 developmental biology, Cell Nucleus, 0303 health sciences, Mutation, Base Sequence, Research, 030302 biochemistry & molecular biology, Reverse Transcription, Molecular biology, Reverse transcriptase, 3. Good health, Cell nucleus, [ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Infectious Diseases, medicine.anatomical_structure, Viral replication, chemistry, Cell culture, DNA, Viral, Codon, Terminator, HIV-1, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Nuclear transport, lcsh:RC581-607, DNA
Abstract

Background The human immunodeficiency virus type 1 (HIV-1) central DNA Flap is generated during reverse transcription as a result of (+) strand initiation at the central polypurine tract (cPPT) and termination after a ca. 100 bp strand displacement at the central termination sequence (CTS). The central DNA Flap is a determinant of HIV-1 nuclear import, however, neither cPPT nor CTS mutations entirely abolish nuclear import and infection. Therefore, to determine whether or not the DNA Flap is essential for HIV-1 nuclear import, we generated double mutant (DM) viruses, combining cPPT and CTS mutations to abolish DNA Flap formation. Results The combination of cPPT and CTS mutations reduced the proportion of viruses forming the central DNA Flap at the end of reverse transcription and further decreased virus infectivity in one-cycle titration assays. The most affected DM viruses were unable to establish a spreading infection in the highly permissive MT4 cell line, nor in human primary peripheral blood mononuclear cells (PBMCs), indicating that the DNA Flap is required for virus replication. Surprisingly, we found that DM viruses still maintained residual nuclear import levels, amounting to 5-15% of wild-type virus, as assessed by viral DNA circle quantification. Alu-PCR quantification of integrated viral genome also indicated 5-10% residual integration levels compared to wild-type virus. Conclusion This work establishes that the central DNA Flap is required for HIV-1 spreading infection but points to a residual DNA Flap independent nuclear import, whose functional significance remains unclear since it is not sufficient to support viral replication.

Published
2011

48. CD8+T cell responsiveness to anti-PD-1 is epigenetically regulated by Suv39h1 in melanomas

Author

Leticia Laura Niborski, Paul Gueguen, Mengliang Ye, Allan Thiolat, Rodrigo Nalio Ramos, Pamela Caudana, Jordan Denizeau, Ludovic Colombeau, Raphaël Rodriguez, Christel Goudot, Jean-Michel Luccarini, Anne Soudé, Bruno Bournique, Pierre Broqua, Luigia Pace, Sylvain Baulande, Christine Sedlik, Jean-Pierre Quivy, Geneviève Almouzni, José L. Cohen, Elina Zueva, Joshua J. Waterfall, Sebastian Amigorena, Eliane Piaggio, Institut Curie [Paris], 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), Chimie biologique des membranes et ciblage thérapeutique (CBMCT - UMR 3666 / U1143), 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), Inventiva [Daix], Dynamique du noyau [Institut Curie], Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), ALMOUZNI, Geneviève, Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de génétique et biologie des cancers (U830), and AMIGORENA, Sebastian

Subjects
Multidisciplinary, [SDV]Life Sciences [q-bio], Programmed Cell Death 1 Receptor, General Physics and Astronomy, General Chemistry, Methyltransferases, CD8-Positive T-Lymphocytes, Lymphocyte Activation, General Biochemistry, Genetics and Molecular Biology, Epigenesis, Genetic, Repressor Proteins, [SDV] Life Sciences [q-bio], Lymphocytes, Tumor-Infiltrating, Humans, Melanoma
Abstract

Tumor-infiltrating CD8 + T cells progressively lose functionality and fail to reject tumors. The underlying mechanism and re-programing induced by checkpoint blockers are incompletely understood. We show here that genetic ablation or pharmacological inhibition of histone lysine methyltransferase Suv39h1 delays tumor growth and potentiates tumor rejection by anti-PD-1. In the absence of Suv39h1, anti-PD-1 induces alternative activation pathways allowing survival and differentiation of IFNγ and Granzyme B producing effector cells that express negative checkpoint molecules, but do not reach final exhaustion. Their transcriptional program correlates with that of melanoma patients responding to immune-checkpoint blockade and identifies the emergence of cytolytic-effector tumor-infiltrating lymphocytes as a biomarker of clinical response. Anti-PD-1 favors chromatin opening in loci linked to T-cell activation, memory and pluripotency, but in the absence of Suv39h1, cells acquire accessibility in cytolytic effector loci. Overall, Suv39h1 inhibition enhances anti-tumor immune responses, alone or combined with anti-PD-1, suggesting that Suv39h1 is an “epigenetic checkpoint” for tumor immunity.

Published
2022

49. Single-cell RNA-seq-based proteogenomics identifies glioblastoma-specific transposable elements encoding HLA-I-presented peptides

Author

Pierre-Emmanuel Bonté, Yago A. Arribas, Antonela Merlotti, Montserrat Carrascal, Jiasi Vicky Zhang, Elina Zueva, Zev A. Binder, Cécile Alanio, Christel Goudot, Sebastian Amigorena, Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Instituto de Investigaciones Biomedicas de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Perelman School of Medicine, University of Pennsylvania, Institut Curie [Paris], AMIGORENA, Sebastian, Institut National de la Santé et de la Recherche Médicale (France), Centre National de la Recherche Scientifique (France), and Ligue Nationale contre le Cancer (France)

Subjects
non-coding genome, cancer immunotherapy, single-cell RNA-seq, [SDV]Life Sciences [q-bio], Histocompatibility Antigens Class I, glioblastoma, immunopeptidomics, General Biochemistry, Genetics and Molecular Biology, neoantigen, [SDV] Life Sciences [q-bio], endogenous retrovirus, non-canonical proteome, DNA Transposable Elements, Humans, HLA-I, RNA-Seq, transposable elements, Peptides, Proteogenomics
Abstract

We analyze transposable elements (TEs) in glioblastoma (GBM) patients using a proteogenomic pipeline that combines single-cell transcriptomics, bulk RNA sequencing (RNA-seq) samples from tumors and healthy-tissue cohorts, and immunopeptidomic samples. We thus identify 370 human leukocyte antigen (HLA)-I-bound peptides encoded by TEs differentially expressed in GBM. Some of the peptides are encoded by repeat sequences from intact open reading frames (ORFs) present in up to several hundred TEs from recent long interspersed nuclear element (LINE)-1, long terminal repeat (LTR), and SVA subfamilies. Other HLA-I-bound peptides are encoded by single copies of TEs from old subfamilies that are expressed recurrently in GBM tumors and not expressed, or very infrequently and at low levels, in healthy tissues (including brain). These peptide-coding, GBM-specific, highly recurrent TEs represent potential tumor-specific targets for cancer immunotherapies., We thank all the U932 members, Olivier Lantz, Maude Delost, Nathalie Amzallag, and Florence Faure, for helpful discussions. Also, we are grateful to Joshua J. Waterfall for helpful discussion and bioinformatics advice. In addition, we thank the core facilities at Curie Institute, including the Bioinformatics groups. S.A. received funding from the Institut Curie, Institut National de la Sante´ et de la Recherche Me´ dicale, and Centre National de la Recherche Scientifique. This work has received support under the program « Investissements d’Avenir » launched by the French Government. We thank the Ligue Nationale Contre Le Cancer for the fellowship to Y.A.A.

Published
2022

50. Homosalate boosts the release of tumour‐derived extracellular vesicles with protection against anchorage‐loss property

Author

Eleonora Grisard, Nathalie Nevo, Aurianne Lescure, Sebastian Doll, Maxime Corbé, Mabel Jouve, Gregory Lavieu, Alain Joliot, Elaine Del Nery, Lorena Martin‐Jaular, Clotilde Théry, Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), BioImaging Cell and Tissue Core Facility (PICT-IBiSA), Institut Curie [Paris], Helmholtz Zentrum München = German Research Center for Environmental Health, Génétique et Biologie du Développement, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de sciences cognitives et psycholinguistique (LSCP), Département d'Etudes Cognitives - ENS Paris (DEC), 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)-École des hautes études en sciences sociales (EHESS)-Centre National de la Recherche Scientifique (CNRS), and Joliot, Alain

Subjects
[SDV] Life Sciences [q-bio], Extracellular Vesicles, Histology, [SDV]Life Sciences [q-bio], Dietary Supplements, Humans, Triple Negative Breast Neoplasms, Cell Biology, Salicylates
Abstract

International audience; Eukaryotic cells, including cancer cells, secrete highly heterogeneous populations of extracellular vesicles (EVs). EVs could have different subcellular origin, composition and functional properties, but tools to distinguish between EV subtypes are scarce. Here, we tagged CD63- or CD9-positive EVs secreted by triple negative breast cancer cells with Nanoluciferase enzyme, to set-up a miniaturized method to quantify secretion of these two EV subtypes directly in the supernatant of cells. We performed a cell-based high-content screening to identify clinically-approved drugs able to affect EV secretion. One of the identified hits is Homosalate, an anti-inflammatory drug found in sunscreens which robustly increased EVs' release. Comparing EVs induced by Homosalate with those induced by Bafilomycin A1, we demonstrate that: (1) the two drugs act on EVs generated in distinct subcellular compartments, and (2) EVs released by Homosalate-, but not by Bafilomycin A1-treated cells enhance resistance to anchorage loss in another recipient epithelial tumour cell line. In conclusion, we identified a new drug modifying EV release and demonstrated that under influence of different drugs, triple negative breast cancer cells release EV subpopulations from different subcellular origins harbouring distinct functional properties.

Published
2022

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