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1. Immune effectors responsible for the elimination of hyperploid cancer cells

Author: Fernando Aranda, Kariman Chaba, Norma Bloy, Pauline Garcia, Chloé Bordenave, Isabelle Martins, Gautier Stoll, Antoine Tesniere, Guido Kroemer, and Laura Senovilla
Subjects: hyperploidy, genomic instability, cancer, immunosurveillance, immunoselection, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: The immune system avoids oncogenesis and slows down tumor progression through a mechanism called immunosurveillance. Nevertheless, some malignant cells manage to escape from immune control and form clinically detectable tumors. Tetraploidy, which consists in the intrinsically unstable duplication of the genome, is considered as a (pre)-cancerous event that can result in aneuploidy and contribute to oncogenesis. We previously described the fact that tetraploid cells can be eliminated by the immune system. Here, we investigate the role of different innate and acquired immune effectors by inoculating hyperploid cancer cells into wild type or mice bearing different immunodeficient genotypes (Cd1d−/−, FcRn−/−, Flt3l−/−, Foxn1nu/nu, MyD88−/−, Nlrp3−/−, Ighmtm1Cgn, Rag2−/−), followed by the monitoring of tumor incidence, growth and final ploidy status. Our results suggest that multiple different immune effectors including B, NK, NKT and T cells, as well as innate immune responses involving the interleukine-1 receptor and the Toll-like receptor systems participate to the immunoselection against hyperploid cells. Hence, optimal anticancer immunosurveillance likely involves the contribution of multiple arms of the immune system.
Published: 2018
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2. Prognostic Impact of Vitamin B6 Metabolism in Lung Cancer

Author: Lorenzo Galluzzi, Ilio Vitale, Laura Senovilla, Ken André Olaussen, Guillaume Pinna, Tobias Eisenberg, Aïcha Goubar, Isabelle Martins, Judith Michels, Gueorgui Kratassiouk, Didac Carmona-Gutierrez, Marie Scoazec, Erika Vacchelli, Frederic Schlemmer, Oliver Kepp, Shensi Shen, Maximilien Tailler, Mireia Niso-Santano, Eugenia Morselli, Alfredo Criollo, Sandy Adjemian, Mohamed Jemaà, Kariman Chaba, Claire Pailleret, Mickaël Michaud, Federico Pietrocola, Nicolas Tajeddine, Thibault de La Motte Rouge, Natalia Araujo, Nadya Morozova, Thomas Robert, Hugues Ripoche, Frederic Commo, Benjamin Besse, Pierre Validire, Pierre Fouret, Angélique Robin, Nicolas Dorvault, Philippe Girard, Sébastien Gouy, Patricia Pautier, Nora Jägemann, Ann-Christin Nickel, Sabrina Marsili, Caroline Paccard, Nicolas Servant, Philippe Hupé, Carmen Behrens, Parviz Behnam-Motlagh, Kimitoshi Kohno, Isabelle Cremer, Diane Damotte, Marco Alifano, Øivind Midttun, Per Magne Ueland, Vladimir Lazar, Philippe Dessen, Hans Zischka, Etienne Chatelut, Maria Castedo, Frank Madeo, Emmanuel Barillot, Juergen Thomale, Ignacio Ivan Wistuba, Catherine Sautès-Fridman, Laurence Zitvogel, Jean-Charles Soria, Annick Harel-Bellan, and Guido Kroemer
Subjects: Biology (General), QH301-705.5
Abstract: Patients with non-small cell lung cancer (NSCLC) are routinely treated with cytotoxic agents such as cisplatin. Through a genome-wide siRNA-based screen, we identified vitamin B6 metabolism as a central regulator of cisplatin responses in vitro and in vivo. By aggravating a bioenergetic catastrophe that involves the depletion of intracellular glutathione, vitamin B6 exacerbates cisplatin-mediated DNA damage, thus sensitizing a large panel of cancer cell lines to apoptosis. Moreover, vitamin B6 sensitizes cancer cells to apoptosis induction by distinct types of physical and chemical stress, including multiple chemotherapeutics. This effect requires pyridoxal kinase (PDXK), the enzyme that generates the bioactive form of vitamin B6. In line with a general role of vitamin B6 in stress responses, low PDXK expression levels were found to be associated with poor disease outcome in two independent cohorts of patients with NSCLC. These results indicate that PDXK expression levels constitute a biomarker for risk stratification among patients with NSCLC.
Published: 2012
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3. Data from Prognostic Value and Relation with Adjuvant Treatment Duration of ctDNA in Stage III Colon Cancer: a Post Hoc Analysis of the PRODIGE-GERCOR IDEA-France Trial

Author: Pierre Laurent-Puig, Thierry André, Dewi Vernerey, Aimery de Gramont, Thibault Mazard, Kariman Chaba, Katia Hormigos, Claire Mulot, Olivier Bouche, Joëlle Egreteau, May Mabro, Céline Lepere, Christophe Louvet, Jérôme Desrame, Jaafar Bennouna, Laurent Mineur, Camille Bourreau, Julie Henriques, Valérie Taly, and Julien Taieb
Abstract: Purpose:Circulating tumor DNA (ctDNA) has been suggested as a major prognostic factor in resected stage-III colon cancer. We analyzed ctDNA of patients randomized in the phase III IDEA-France trial.Experimental Design:ctDNA was tested for WIF1 and NPY by droplet digital PCR with method developed and validated for colorectal cancer. Disease-free survival (DFS) and overall survival (OS) were analyzed via multivariable analysis in patients with ctDNA samples and in sub-groups according to treatment duration (3/6 months) and disease stage (high/low-risk stage III).Results:Of 2,010 randomized patients, 1,345 had available ctDNA samples (1,017 collected both post-surgery and pre-chemotherapy). More Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 (78% versus 69%) and T4 and/or N2 (40% versus 36%) were observed in patients studied (n = 1017) versus not analyzed (n = 993). There were 877 ctDNA-negative (86.2%) and 140 ctDNA-positive (13.8%) patients; their baseline characteristics were similar. With a median follow-up of 6.6 years, the 3-year DFS rate was 66.39% for ctDNA-positive patients and 76.71% for ctDNA-negative patients (P = 0.015). ctDNA was confirmed as an independent prognostic marker for DFS (adjusted HR = 1.55, 95% CI 1.13–2.12, P = 0.006) and OS (HR = 1.65, 95% CI 1.12–2.43, P = 0.011). ctDNA was prognostic in patients treated for 3 months and with T4 and/or N2 tumors, but not in those treated for 6 months and with T1–3/N1 tumors.Conclusions:In this first ctDNA assessment of a large series of patients with stage III colon cancer enrolled in phase III trial, post-surgery ctDNA was found in 13.8% of them and was confirmed as an independent prognostic marker.See related commentary by Bent and Kopetz, p. 5449
Published: 2023
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4. Supplementary Data from Prognostic Value and Relation with Adjuvant Treatment Duration of ctDNA in Stage III Colon Cancer: a Post Hoc Analysis of the PRODIGE-GERCOR IDEA-France Trial

Author: Pierre Laurent-Puig, Thierry André, Dewi Vernerey, Aimery de Gramont, Thibault Mazard, Kariman Chaba, Katia Hormigos, Claire Mulot, Olivier Bouche, Joëlle Egreteau, May Mabro, Céline Lepere, Christophe Louvet, Jérôme Desrame, Jaafar Bennouna, Laurent Mineur, Camille Bourreau, Julie Henriques, Valérie Taly, and Julien Taieb
Abstract: Supplementary Data
Published: 2023
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5. Supplementary Figure 3 from Regulation of CD4+NKG2D+ Th1 Cells in Patients with Metastatic Melanoma Treated with Sorafenib: Role of IL-15Rα and NKG2D Triggering

Author: Laurence Zitvogel, Caroline Robert, Alexander Eggermont, Danila Valmori, Maha Ayyoub, Christine Mateus, Camillo Porta, Philippe Dessen, Philippe Vielh, Anne Aupérin, Meriem Messaoudene, Anne Caignard, Caroline Flament, Sophie Caillat-Zucman, Yannick Jacques, Erwan Mortier, Kariman Chaba, Nicolas Jacquelot, Sylvie Rusakiewicz, Vichnou Poirier-Colame, Nathalie Chaput, and Ana I. Romero
Abstract: PDF file - 109K, CD4+CD8dim or CD4+NKG2D+ T cells can be found in other malignancies.
Published: 2023
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6. Supplementary Figure 2 from Regulation of CD4+NKG2D+ Th1 Cells in Patients with Metastatic Melanoma Treated with Sorafenib: Role of IL-15Rα and NKG2D Triggering

Author: Laurence Zitvogel, Caroline Robert, Alexander Eggermont, Danila Valmori, Maha Ayyoub, Christine Mateus, Camillo Porta, Philippe Dessen, Philippe Vielh, Anne Aupérin, Meriem Messaoudene, Anne Caignard, Caroline Flament, Sophie Caillat-Zucman, Yannick Jacques, Erwan Mortier, Kariman Chaba, Nicolas Jacquelot, Sylvie Rusakiewicz, Vichnou Poirier-Colame, Nathalie Chaput, and Ana I. Romero
Abstract: PDF file - 84K, The combination therapy induced a profound lymphopenia.
Published: 2023
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7. Supplementary Figure 4 from Regulation of CD4+NKG2D+ Th1 Cells in Patients with Metastatic Melanoma Treated with Sorafenib: Role of IL-15Rα and NKG2D Triggering

Author: Laurence Zitvogel, Caroline Robert, Alexander Eggermont, Danila Valmori, Maha Ayyoub, Christine Mateus, Camillo Porta, Philippe Dessen, Philippe Vielh, Anne Aupérin, Meriem Messaoudene, Anne Caignard, Caroline Flament, Sophie Caillat-Zucman, Yannick Jacques, Erwan Mortier, Kariman Chaba, Nicolas Jacquelot, Sylvie Rusakiewicz, Vichnou Poirier-Colame, Nathalie Chaput, and Ana I. Romero
Abstract: PDF file - 38K, Synergistic effects of TCR or IL-15 stimulation with NKG2D engagement for Th1 polarization in CD4+NKG2D+T cells.
Published: 2023
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8. Supplementary Figure 6 from Regulation of CD4+NKG2D+ Th1 Cells in Patients with Metastatic Melanoma Treated with Sorafenib: Role of IL-15Rα and NKG2D Triggering

Author: Laurence Zitvogel, Caroline Robert, Alexander Eggermont, Danila Valmori, Maha Ayyoub, Christine Mateus, Camillo Porta, Philippe Dessen, Philippe Vielh, Anne Aupérin, Meriem Messaoudene, Anne Caignard, Caroline Flament, Sophie Caillat-Zucman, Yannick Jacques, Erwan Mortier, Kariman Chaba, Nicolas Jacquelot, Sylvie Rusakiewicz, Vichnou Poirier-Colame, Nathalie Chaput, and Ana I. Romero
Abstract: PDF file - 94K, 2D Clustering of LogRatios (D21/D0) of gene expression post- (D21) and pre-therapy (D0) with sorafenib/temozolomide.
Published: 2023
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9. Supplementary Figure 5 from Regulation of CD4+NKG2D+ Th1 Cells in Patients with Metastatic Melanoma Treated with Sorafenib: Role of IL-15Rα and NKG2D Triggering

Author: Laurence Zitvogel, Caroline Robert, Alexander Eggermont, Danila Valmori, Maha Ayyoub, Christine Mateus, Camillo Porta, Philippe Dessen, Philippe Vielh, Anne Aupérin, Meriem Messaoudene, Anne Caignard, Caroline Flament, Sophie Caillat-Zucman, Yannick Jacques, Erwan Mortier, Kariman Chaba, Nicolas Jacquelot, Sylvie Rusakiewicz, Vichnou Poirier-Colame, Nathalie Chaput, and Ana I. Romero
Abstract: PDF file - 1795K, T-cell infiltration and MICA/B expression in metastatic melanoma.
Published: 2023
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10. Supplementary Tables 1 - 3, Figures 1 - 2 from Immune Infiltrates Are Prognostic Factors in Localized Gastrointestinal Stromal Tumors

Author: Laurence Zitvogel, Jean-Yves Blay, Axel Le Cesne, Nathalie Chaput, Guido Kroemer, Jean-Michel Coindre, Jean-François Emile, Paule Opolon, Philippe Terrier, Frédéric Commo, Sylvie Bonvalot, Alexander Eggermont, Dirk Jäger, Niels Halama, Caroline Flament, Kariman Chaba, Vichnou Poirier-Colame, Anne Caignard, Isabelle Cremer, Patrice Dubreuil, Valérie Le Brun-Ly, Loic Chaigneau, Nicolas Isambert, Federico Garrido, Angel Concha, Nadège Vimond, Rosa Mendez, Clara Locher, Mélanie Desbois, Matthieu Sarabi, Michaela Semeraro, and Sylvie Rusakiewicz
Abstract: PDF file - 197K, Supplemental Table 1. Characteristics of GIST patients for the immunohistochemistry study. Supplemental Table 2. Characteristics of GIST and STS patients studied in flow cytometry. Supplemental Table 3: Antibodies for flow cytometry and IHC. Supplemental Figure 1. Correlation between T and NK cell infiltrates and the 3-digit Miettinen score. Supplemental Figure 2. GIST TIls are mainly composed of CD4+ T cells.
Published: 2023
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11. Data from Regulation of CD4+NKG2D+ Th1 Cells in Patients with Metastatic Melanoma Treated with Sorafenib: Role of IL-15Rα and NKG2D Triggering

Author: Laurence Zitvogel, Caroline Robert, Alexander Eggermont, Danila Valmori, Maha Ayyoub, Christine Mateus, Camillo Porta, Philippe Dessen, Philippe Vielh, Anne Aupérin, Meriem Messaoudene, Anne Caignard, Caroline Flament, Sophie Caillat-Zucman, Yannick Jacques, Erwan Mortier, Kariman Chaba, Nicolas Jacquelot, Sylvie Rusakiewicz, Vichnou Poirier-Colame, Nathalie Chaput, and Ana I. Romero
Abstract: Beyond cancer-cell intrinsic factors, the immune status of the host has a prognostic impact on patients with cancer and influences the effects of conventional chemotherapies. Metastatic melanoma is intrinsically immunogenic, thereby facilitating the search for immune biomarkers of clinical responses to cytotoxic agents. Here, we show that a multi-tyrosine kinase inhibitor, sorafenib, upregulates interleukin (IL)-15Rα in vitro and in vivo in patients with melanoma, and in conjunction with natural killer (NK) group 2D (NKG2D) ligands, contributes to the Th1 polarization and accumulation of peripheral CD4+NKG2D+ T cells. Hence, the increase of blood CD4+NKG2D+ T cells after two cycles of sorafenib (combined with temozolomide) was associated with prolonged survival in a prospective phase I/II trial enrolling 63 patients with metastatic melanoma who did not receive vemurafenib nor immune checkpoint–blocking antibodies. In contrast, in metastatic melanoma patients treated with classical treatment modalities, this CD4+NKG2D+ subset failed to correlate with prognosis. These findings indicate that sorafenib may be used as an “adjuvant” molecule capable of inducing or restoring IL-15Rα/IL-15 in tumors expressing MHC class I–related chain A/B (MICA/B) and on circulating monocytes of responding patients, hereby contributing to the bioactivity of NKG2D+ Th1 cells. Cancer Res; 74(1); 68–80. ©2013 AACR.
Published: 2023
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12. Supplementary Figure 1 from Regulation of CD4+NKG2D+ Th1 Cells in Patients with Metastatic Melanoma Treated with Sorafenib: Role of IL-15Rα and NKG2D Triggering

Author: Laurence Zitvogel, Caroline Robert, Alexander Eggermont, Danila Valmori, Maha Ayyoub, Christine Mateus, Camillo Porta, Philippe Dessen, Philippe Vielh, Anne Aupérin, Meriem Messaoudene, Anne Caignard, Caroline Flament, Sophie Caillat-Zucman, Yannick Jacques, Erwan Mortier, Kariman Chaba, Nicolas Jacquelot, Sylvie Rusakiewicz, Vichnou Poirier-Colame, Nathalie Chaput, and Ana I. Romero
Abstract: PDF file - 25K, Schedule of the sorafenib and temozolomide combination regimen.
Published: 2023
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13. Supplementary Figure Legend from Regulation of CD4+NKG2D+ Th1 Cells in Patients with Metastatic Melanoma Treated with Sorafenib: Role of IL-15Rα and NKG2D Triggering

Author: Laurence Zitvogel, Caroline Robert, Alexander Eggermont, Danila Valmori, Maha Ayyoub, Christine Mateus, Camillo Porta, Philippe Dessen, Philippe Vielh, Anne Aupérin, Meriem Messaoudene, Anne Caignard, Caroline Flament, Sophie Caillat-Zucman, Yannick Jacques, Erwan Mortier, Kariman Chaba, Nicolas Jacquelot, Sylvie Rusakiewicz, Vichnou Poirier-Colame, Nathalie Chaput, and Ana I. Romero
Abstract: PDF file - 119K
Published: 2023
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14. Prognostic Value and Relation with Adjuvant Treatment Duration of ctDNA in Stage III Colon Cancer: a Post Hoc Analysis of the PRODIGE-GERCOR IDEA-France Trial

Author: Pierre Laurent-Puig, May Mabro, Valérie Taly, Jaafar Bennouna, Claire Mulot, Julie Henriques, Olivier Bouché, Jérôme Desramé, Joëlle Egreteau, Thibault Mazard, C. Lepere, Laurent Mineur, Christophe Louvet, Dewi Vernerey, Camille Bourreau, Kariman Chaba, Aimery de Gramont, Katia Hormigos, Julien Taieb, Thierry André, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), 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 de Paris (UP), Cancer Research and Personalized Medicine - CARPEM [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Saint-Jacques [CHRU de Besançon], Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), 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]), Institut Sainte Catherine [Avignon], Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital privé Jean-Mermoz [Lyon] (Ramsay-GDS), Institut Mutualiste de Montsouris (IMM), Hôpital Foch [Suresnes], Groupe Hospitalier Bretagne Sud (GHBS), Hôpital Robert Debré, 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), Institut hospitalier Franco-Britannique [Levallois-Perret], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), TALY, Valerie, 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), 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 Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)
Subjects: Cancer Research, medicine.medical_specialty, Colorectal cancer, medicine.medical_treatment, Treatment duration, [SDV]Life Sciences [q-bio], Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Post-hoc analysis, medicine, In patient, Stage (cooking), 030304 developmental biology, 0303 health sciences, business.industry, medicine.disease, 3. Good health, Stage III Colon Cancer, [SDV] Life Sciences [q-bio], Oncology, 030220 oncology & carcinogenesis, Baseline characteristics, business, Adjuvant
Abstract: Purpose:Circulating tumor DNA (ctDNA) has been suggested as a major prognostic factor in resected stage-III colon cancer. We analyzed ctDNA of patients randomized in the phase III IDEA-France trial.Experimental Design:ctDNA was tested for WIF1 and NPY by droplet digital PCR with method developed and validated for colorectal cancer. Disease-free survival (DFS) and overall survival (OS) were analyzed via multivariable analysis in patients with ctDNA samples and in sub-groups according to treatment duration (3/6 months) and disease stage (high/low-risk stage III).Results:Of 2,010 randomized patients, 1,345 had available ctDNA samples (1,017 collected both post-surgery and pre-chemotherapy). More Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 (78% versus 69%) and T4 and/or N2 (40% versus 36%) were observed in patients studied (n = 1017) versus not analyzed (n = 993). There were 877 ctDNA-negative (86.2%) and 140 ctDNA-positive (13.8%) patients; their baseline characteristics were similar. With a median follow-up of 6.6 years, the 3-year DFS rate was 66.39% for ctDNA-positive patients and 76.71% for ctDNA-negative patients (P = 0.015). ctDNA was confirmed as an independent prognostic marker for DFS (adjusted HR = 1.55, 95% CI 1.13–2.12, P = 0.006) and OS (HR = 1.65, 95% CI 1.12–2.43, P = 0.011). ctDNA was prognostic in patients treated for 3 months and with T4 and/or N2 tumors, but not in those treated for 6 months and with T1–3/N1 tumors.Conclusions:In this first ctDNA assessment of a large series of patients with stage III colon cancer enrolled in phase III trial, post-surgery ctDNA was found in 13.8% of them and was confirmed as an independent prognostic marker.See related commentary by Bent and Kopetz, p. 5449
Published: 2021
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15. 18F-FDG PET metabolic-to-morphological volume ratio predicts PD-L1 tumour expression and response to PD-1 blockade in non-small-cell lung cancer

Author: Kariman Chaba, Niklaus Schaefer, Lana E. Kandalaft, Solange Peters, Sylvie Rusakiewicz, Marie Nicod-Lalonde, Pedro Romero, de Leval L, Cristina, John O. Prior, Renaud S, George Coukos, Mario Jreige, Thorsten Krueger, and Igor Letovanec
Subjects: PET-CT, Pathology, medicine.medical_specialty, Necrosis, Imaging biomarker, medicine.diagnostic_test, business.industry, Standardized uptake value, General Medicine, medicine.disease, 030218 nuclear medicine & medical imaging, Lesion, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Biopsy, Medicine, Immunohistochemistry, Radiology, Nuclear Medicine and imaging, medicine.symptom, business, Lung cancer
Abstract: Anti-PD-1/PD-L1 blockade can restore tumour-specific T-cell immunity and is an emerging therapy in non-small-cell lung cancer (NSCLC). We investigated the correlation between 18F-FDG PET/CT-based markers and tumour tissue expression of PD-L1, necrosis and clinical outcome in patients receiving checkpoint inhibitor treatment. PD-Li expression in biopsy or resection specimens from 49 patients with confirmed NSCLC was investigated by immunohistochemistry. Maximum standardized uptake value (SUVmax), mean SUV (SUVmean), metabolic tumour volume (MTV) and total lesion glycolysis (TLG) were obtained from 18F-FDG PET/CT images. The ratio of metabolic to morphological lesion volumes (MMVR) and its association with PD-L1 expression in each lesion were calculated. The associations between histologically reported necrosis and 18F-FDG PET imaging patterns and radiological outcome (evaluated by iRECIST) following anti-PD-1/PD-L1 therapy were also analysed. In 14 patients, the association between necrosis and MMVR and tumour immune contexture were analysed by multiple immunofluorescent (IF) staining for CD8, PD-1, granzyme B (GrzB) and NFATC2. In total, 25 adenocarcinomas and 24 squamous cell carcinomas were analysed. All tumours showed metabolic 18F-FDG PET uptake. MMVR was correlated inversely with PD-L1 expression in tumour cells. Furthermore, PD-L1 expression and low MMVR were significantly correlated with clinical benefit. Necrosis was correlated negatively with MMVR. Multiplex IF staining showed a greater frequency of activated CD8+ cells in necrotic tumours than in nonnecrotic tumours in both stromal and epithelial tumour compartments. This study introduces MMVR as a new imaging biomarker and its ability to noninvasively capture increased PD-L1 tumour expression and predict clinical benefit from checkpoint blockade in NSCLC should be further evaluated.
Published: 2019
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16. Prognostic Value and Relation with Adjuvant Treatment Duration of ctDNA in Stage III Colon Cancer: a

Author: Julien, Taieb, Valérie, Taly, Julie, Henriques, Camille, Bourreau, Laurent, Mineur, Jaafar, Bennouna, Jérôme, Desrame, Christophe, Louvet, Céline, Lepere, May, Mabro, Joëlle, Egreteau, Olivier, Bouche, Claire, Mulot, Katia, Hormigos, Kariman, Chaba, Thibault, Mazard, Aimery, de Gramont, Dewi, Vernerey, Thierry, André, and Pierre, Laurent-Puig
Subjects: Male, Duration of Therapy, Chemotherapy, Adjuvant, Colonic Neoplasms, Humans, Female, Prospective Studies, Prognosis, Disease-Free Survival, Article, Aged, Circulating Tumor DNA, Neoplasm Staging
Abstract: Circulating tumor DNA (ctDNA) has been suggested as a major prognostic factor in resected stage-III colon cancer. We analyzed ctDNA of patients randomized in the phase III IDEA-France trial.ctDNA was tested forOf 2,010 randomized patients, 1,345 had available ctDNA samples (1,017 collected both post-surgery and pre-chemotherapy). More Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 (78% versus 69%) and T4 and/or N2 (40% versus 36%) were observed in patients studied (In this first ctDNA assessment of a large series of patients with stage III colon cancer enrolled in phase III trial, post-surgery ctDNA was found in 13.8% of them and was confirmed as an independent prognostic marker.
Published: 2021

17. Combined evaluation of LC3B puncta and HMGB1 expression predicts residual risk of relapse after adjuvant chemotherapy in breast cancer

Author: Laurent Arnould, Sylvain Ladoire, David Enot, Laura Senovilla, Marie Laure Poillot, Aicha Goubar, Patrick Arveux, Laurence Zitvogel, Suzette Delaloge, C. Dalban, François Ghiringhelli, Frédérique Penault-Llorca, Nicole Prada, Fabrice Andre, Guido Kroemer, Vichnou Poirier-Colame, Clara Locher, Pierre Fumoleau, Marc Spielmann, and Kariman Chaba
Subjects: Oncology, medicine.medical_specialty, Anthracycline, medicine.medical_treatment, Breast Neoplasms, Biology, Breast cancer, Recurrence, Risk Factors, Internal medicine, Autophagy, Biomarkers, Tumor, medicine, Humans, HMGB1 Protein, Molecular Biology, Chemotherapy, Hazard ratio, Cell Biology, medicine.disease, Confidence interval, Gene Expression Regulation, Neoplastic, Chemotherapy, Adjuvant, Immunology, Cohort, Cancer cell, Immunohistochemistry, Female, Clinical Research Paper, Microtubule-Associated Proteins
Abstract: In spite of adjuvant chemotherapy, a significant fraction of patients with localized breast cancer (BC) relapse after optimal treatment. We determined the occurrence of cytoplasmic MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3B)-positive puncta, as well as the presence of nuclear HMGB1 (high mobility group box 1) in cancer cells within surgical BC specimens by immunohistochemistry, first in a test cohort (152 patients) and then in a validation cohort of localized BC patients who all received adjuvant anthracycline-based chemotherapy (1646 patients). Cytoplasmic LC3B(+) puncta inversely correlated with the intensity of SQSTM1 staining, suggesting that a high percentage cells of LC3B(+) puncta reflects increased autophagic flux. After setting optimal thresholds in the test cohort, cytoplasmic LC3B(+) puncta and nuclear HMGB1 were scored as positive in 27.2% and 28.6% of the tumors, respectively, in the validation cohort, while 8.7% were considered as double positive. LC3B(+) puncta or HMGB1 expression alone did not constitute independent prognostic factors for metastasis-free survival (MFS) in multivariate analyses. However, the combined positivity for LC3B(+) puncta and nuclear HMGB1 constituted an independent prognostic factor significantly associated with prolonged MFS (hazard ratio: 0.49 95% confidence interval [0.26-0.89]; P = 0.02), and improved breast cancer specific survival (hazard ratio: 0.21 95% confidence interval [0.05-0.85]; P = 0.029). Subgroup analyses revealed that within patients with poor-prognosis BC, HMGB1(+) LC3B(+) double-positive tumors had a better prognosis than BC that lacked one or both of these markers. Altogether, these results suggest that the combined positivity for LC3B(+) puncta and nuclear HMGB1 is a positive predictor for longer BC survival.
Published: 2015
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18. Negative prognostic impact of regulatory T cell infiltration in surgically resected esophageal cancer post-radiochemotherapy

Author: Aurélie Perier, Michaela Semeraro, C. Gronnier, Peggy Dartigues, David Enot, Kariman Chaba, Irène Villa, Laurence Zitvogel, Vichnou Poirier Colame, Sylvie Rusakiewicz, Erika Vacchelli, Christophe Mariette, Guido Kroemer, and Diane Goéré
Subjects: Male, Pathology, medicine.medical_specialty, autophagy, Esophageal Neoplasms, Genotype, Colorectal cancer, Regulatory T cell, pattern recognition receptor, ATG16L1, Biology, CD8-Positive T-Lymphocytes, T-Lymphocytes, Regulatory, Cohort Studies, Lymphocytes, Tumor-Infiltrating, immunogenic cell death, medicine, Cytotoxic T cell, Humans, Alleles, apoptosis, FOXP3, Forkhead Transcription Factors, Chemoradiotherapy, Esophageal cancer, medicine.disease, Prognosis, Immunohistochemistry, Immunosurveillance, Gene Expression Regulation, Neoplastic, Toll-Like Receptor 4, medicine.anatomical_structure, Treatment Outcome, Oncology, Cancer research, Female, Receptors, Purinergic P2X7, CD8, Priority Research Paper
Abstract: Ever accumulating evidence indicates that the long-term effects of radiotherapy and chemotherapy largely depend on the induction (or restoration) of an anticancer immune response. Here, we investigated this paradigm in the context of esophageal carcinomas treated by neo-adjuvant radiochemotherapy, in a cohort encompassing 196 patients. We found that the density of the FOXP3+ regulatory T cell (Treg) infiltrate present in the residual tumor (or its scar) correlated with the pathological response (the less Tregs the more pronounced was the histological response) and predicted cancer-specific survival. In contrast, there was no significant clinical impact of the frequency of CD8+ cytotoxic T cells. At difference with breast or colorectal cancer, a loss-of-function allele of toll like receptor 4 (TLR4) improved cancer-specific survival of patients with esophageal cancer. While a loss-of-function allele of purinergic receptor P2X, ligand-gated ion channel, 7 (P2RX7) failed to affect cancer-specific survival, its presence did correlate with an increase in Treg infiltration. Altogether, these results corroborate the notion that the immunosurveillance seals the fate of patients with esophageal carcinomas treated with conventional radiochemotherapy.
Published: 2015

19. Immune effectors responsible for the elimination of hyperploid cancer cells

Author: Laura Senovilla, Fernando Aranda, Norma Bloy, Isabelle Martins, Chloé Bordenave, Antoine Tesniere, Guido Kroemer, Pauline Garcia, Kariman Chaba, and Gautier Stoll
Subjects: lcsh:Immunologic diseases. Allergy, 0301 basic medicine, Genome instability, Immunology, hyperploidy, immunosurveillance, chemical and pharmacologic phenomena, Biology, medicine.disease_cause, lcsh:RC254-282, 03 medical and health sciences, Immune system, Gene duplication, medicine, cancer, Immunology and Allergy, immunoselection, Original Research, Innate immune system, genomic instability, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Immunosurveillance, 030104 developmental biology, Oncology, Tumor progression, Cancer cell, Cancer research, lcsh:RC581-607, Carcinogenesis
Abstract: The immune system avoids oncogenesis and slows down tumor progression through a mechanism called immunosurveillance. Nevertheless, some malignant cells manage to escape from immune control and form clinically detectable tumors. Tetraploidy, which consists in the intrinsically unstable duplication of the genome, is considered as a (pre)-cancerous event that can result in aneuploidy and contribute to oncogenesis. We previously described the fact that tetraploid cells can be eliminated by the immune system. Here, we investigate the role of different innate and acquired immune effectors by inoculating hyperploid cancer cells into wild type or mice bearing different immunodeficient genotypes (Cd1d(−/−), FcRn(−/−), Flt3l(−/−), Foxn1(nu/nu), MyD88(−/−), Nlrp3(−)(/)(−), Ighm(tm1Cgn), Rag2(−/−)), followed by the monitoring of tumor incidence, growth and final ploidy status. Our results suggest that multiple different immune effectors including B, NK, NKT and T cells, as well as innate immune responses involving the interleukine-1 receptor and the Toll-like receptor systems participate to the immunoselection against hyperploid cells. Hence, optimal anticancer immunosurveillance likely involves the contribution of multiple arms of the immune system.
Published: 2018

20. Unsaturated fatty acids induce non‐canonical autophagy

Author: Frank Madeo, V. Izzo, Rodrigo Troncoso, Nektarios Tavernarakis, Nicolas Dupont, Maria Chiara Maiuri, Gérard Pierron, Patrice Codogno, Amena BenYounès, Maria Markaki, Patrick Rockenfeller, Francesco Cecconi, Guillermo Mariño, Mireia Niso-Santano, José Manuel Bravo-San Pedro, Sergio Lavandero, Shoaib Ahmad Malik, Federico Pietrocola, Guido Kroemer, Chantal Bauvy, Oliver Kepp, Kariman Chaba, Valentina Cianfanelli, Lorenzo Galluzzi, Valentina Sica, Heimo Wolinski, Francis Harper, Niso Santano, Mireia, Malik, Shoaib Ahmad, Pietrocola, Federico, Bravo San Pedro, José Manuel, Mariño, Guillermo, Cianfanelli, Valentina, Ben Younès, Amena, Troncoso, Rodrigo, Markaki, Maria, Sica, Valentina, Izzo, Valentina, Chaba, Kariman, Bauvy, Chantal, Dupont, Nicola, Kepp, Oliver, Rockenfeller, Patrick, Wolinski, Heimo, Madeo, Frank, Lavandero, Sergio, Codogno, Patrice, Harper, Franci, Pierron, Gérard, Tavernarakis, Nektario, Cecconi, Francesco, Maiuri, MARIA CHIARA, Galluzzi, Lorenzo, and Kroemer, Guido
Subjects: Autophagy, Fatty Acids, ATG5, LC3, Beclin 1, Palmitic Acid, Inbred C57BL, Transgenic, Palmitic acid, ATG5, GFP‐LC3, RFP‐FYVE, beclin 1, brefeldin A, Animals, Apoptosis Regulatory Proteins, Autophagy, Caenorhabditis elegans, Cells, Cultured, Fatty Acids, Unsaturated, Female, HeLa Cells, Humans, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Transgenic, Oleic Acid, Saccharomyces cerevisiae, Up-Regulation, chemistry.chemical_compound, Unsaturated, Cultured, General Neuroscience, Fatty Acids, BECN1, Brefeldin A, Cell biology, Biochemistry, symbols, Beclin-1, Settore BIO/06, Cells, Biology, General Biochemistry, Genetics and Molecular Biology, symbols.namesake, Lipolysis, Molecular Biology, General Immunology and Microbiology, AMPK, Golgi apparatus, Have You Seen?, chemistry
Abstract: To obtain mechanistic insights into the cross talk between lipolysis and autophagy, two key metabolic responses to starvation, we screened the autophagy-inducing potential of a panel of fatty acids in human cancer cells. Both saturated and unsaturated fatty acids such as palmitate and oleate, respectively, triggered autophagy, but the underlying molecular mechanisms differed. Oleate, but not palmitate, stimulated an autophagic response that required an intact Golgi apparatus. Conversely, autophagy triggered by palmitate, but not oleate, required AMPK, PKR and JNK1 and involved the activation of the BECN1/PIK3C3 lipid kinase complex. Accordingly, the downregulation of BECN1 and PIK3C3 abolished palmitate-induced, but not oleate-induced, autophagy in human cancer cells. Moreover, Becn1(+/-) mice as well as yeast cells and nematodes lacking the ortholog of human BECN1 mounted an autophagic response to oleate, but not palmitate. Thus, unsaturated fatty acids induce a non-canonical, phylogenetically conserved, autophagic response that in mammalian cells relies on the Golgi apparatus.
Published: 2015
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21. Immune-dependent antineoplastic effects of cisplatin plus pyridoxine in non-small-cell lung cancer

Author: Norma Bloy, Mikael J. Pittet, Christina Pfirschke, Fernando Aranda, Laurence Zitvogel, Allan Sauvat, Guido Kroemer, Oliver Kepp, David Enot, B Petit, Laura Senovilla, N Khadra, Kariman Chaba, and J Pesquet
Subjects: Cancer Research, Lung Neoplasms, Context (language use), Mice, SCID, Pharmacology, Mice, Immune system, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Genetics, medicine, Animals, Lung cancer, neoplasms, Molecular Biology, Cisplatin, biology, Pyridoxine, Cancer, Drug Synergism, Endoplasmic Reticulum Stress, medicine.disease, Xenograft Model Antitumor Assays, respiratory tract diseases, biology.protein, Immunogenic cell death, Drug Therapy, Combination, Calreticulin, Neoplasm Transplantation, medicine.drug
Abstract: cis-Diamminedichloroplatinum(II) (CDDP), which is mostly referred to as cisplatin, is a widely used antineoplastic. The efficacy of cisplatin can be improved by combining it with the vitamin B6 precursor pyridoxine. Here, we evaluated the putative synergistic interaction of CDDP with pyridoxine in the treatment of an orthotopic mouse model of non-small-cell lung cancer (NSCLC). CDDP and pyridoxine exhibited hyperadditive therapeutic effects. However, this synergy was only observed in the context of an intact immune system and disappeared when the otherwise successful drug combination was applied to the same NSCLC cancer implanted in the lungs of athymic mice (which lack T lymphocytes). Immunocompetent mice that had been cured from NSCLC by the combined regimen of CDDP plus pyridoxine became resistant against subcutaneous rechallenge with the same (but not with an unrelated) cancer cell line. In vitro, CDDP and pyridoxine did not only cause synergistic killing of NSCLC cells but also elicited signs of immunogenic cell death including an endoplasmic reticulum stress response and exposure of calreticulin at the surface of the NSCLC cells. NSCLC cells treated with CDDP plus pyridoxine in vitro elicited a protective anticancer immune response upon their injection into immunocompetent mice. Altogether, these results suggest that the combined regimen of cisplatin plus pyridoxine mediates immune-dependent antineoplastic effects against NSCLC.
Published: 2014
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22. Antiapoptotic activity of argon and xenon

Author: Jan Pype, Kariman Chaba, Marc Lemaire, Guido Kroemer, Oliver Kepp, Santiago Rello-Varona, Sandy Adjemian, Sabrina Spaggiari, Lorenzo Galluzzi, 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), Apoptose, cancer et immunité (U848), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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 ), Apoptose, cancer et immunité ( U848 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de Chimie et Biochimie Moléculaires et Supramoléculaires ( ICBMS ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École Supérieure Chimie Physique Électronique de Lyon-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 de Lyon-Université de Lyon-École Supérieure de Chimie Physique Électronique de Lyon (CPE)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Xenon, Cell Survival, Cell Culture Techniques, chemistry.chemical_element, Apoptosis, Biology, Oxygen, 03 medical and health sciences, Neon, 0302 clinical medicine, [ CHIM.ORGA ] Chemical Sciences/Organic chemistry, Cell Line, Tumor, Report, medicine, Humans, Staurosporine, Argon, Molecular Biology, 030304 developmental biology, antimycin A, menadione, mitochondrial membrane permeabilization, rotenone, 0303 health sciences, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Cytochrome c, Krypton, Cytochromes c, Cell Biology, U2OS cells, Z-VAD-fmk, Cytosol, Microscopy, Fluorescence, chemistry, Biochemistry, Cytoprotection, 13. Climate action, Biophysics, biology.protein, Mitoxantrone, 030217 neurology & neurosurgery, Developmental Biology, medicine.drug
Abstract: International audience; Although chemically non-reactive, inert noble gases may influence multiple physiological and pathological processes via hitherto uncharacterized physical effects. Here we report a cell-based detection system for assessing the effects of pre-defined gas mixtures on the induction of apoptotic cell death. In this setting, the conventional atmosphere for cell culture was substituted with gas combinations, including the same amount of oxygen (20%) and carbon dioxide (5%) but 75% helium, neon, argon, krypton, or xenon instead of nitrogen. The replacement of nitrogen with noble gases per se had no effects on the viability of cultured human osteosarcoma cells in vitro. Conversely, argon and xenon (but not helium, neon, and krypton) significantly limited cell loss induced by the broad-spectrum tyrosine kinase inhibitor staurosporine, the DNA-damaging agent mitoxantrone and several mitochondrial toxins. Such cytoprotective effects were coupled to the maintenance of mitochondrial integrity, as demonstrated by means of a mitochondrial transmembrane potential-sensitive dye and by assessing the release of cytochrome c into the cytosol. In line with this notion, argon and xenon inhibited the apoptotic activation of caspase-3, as determined by immunofluorescence microscopy coupled to automated image analysis. The antiapoptotic activity of argon and xenon may explain their clinically relevant cytoprotective effects.
Published: 2013
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23. NKp30 isoforms and NKp30 ligands are predictive biomarkers of response to imatinib mesylate in metastatic GIST patients

Author: Serge Leyvraz, Katrin S. Reiners, Christos Christidis, Jean-Yves Blay, Jonathan M. Pitt, Marion Lambert, Aurélien Marabelle, Frédéric Vély, Alexandre Ivagnes, Jean-François Emile, Christian Auclair, Benedita Rocha, Axel Le Cesne, Loic Chaigneau, Christelle Piperoglou, Kariman Chaba, Philippe Terrier, Eric Vivier, Nicolas Isambert, Julien Adam, Sylvie Rusakiewicz, Pierre Validire, Bruno Landi, Thierry Perniceni, Laurence Zitvogel, Sarah Jegou, Sylvie Bonvalot, Michaela Semeraro, Sophie Caillat-Zucman, David Enot, Sandrine Aspeslagh, Aurélie Perier, Christophe Borg, Vichnou Poirier-Colame, Anne Berger, Alexander M.M. Eggermont, Antoine Toubert, Niels Halama, Joachim Koch, Elke Pogge von Strandmann, Olivier Mir, Julien Domont, Anne Caignard, Jean-Michel Coindre, 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), CHU Necker - Enfants Malades [AP-HP], Institut Gustave Roussy (IGR), Université Paris-Sud 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Saclay, Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), Laboratoire d'Immunologie [Hôpital de la Conception - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION )-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), Service d'Immunologie [AP-HM], Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), Microorganismes, Molécules Bioactives et Physiopathologie Intestinale (LBM-E4), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de rhumatologie, inflammation-immunopathologie- biothérapie [CHU Saint-Antoine] (DHU i2B ), CHU Saint-Antoine [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service d'oncologie Médicale, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Departement d'Anatomopathologie, Institut Mutualiste de Montsouris (IMM), Hellenic Open University [Patras], Département de chirurgie digestive, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)-Université de Montpellier (UM), Département d'oncologie médicale [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Centre Jean-bernard, Département de biologie et pathologie médicales [Gustave Roussy], Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Service de Pathologie, Institut Bergonié, Service de pathologie [CHU Ambroise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Ambroise Paré, Immunologie et Cancérologie Intégratives (CRC - Inserm U1138), Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Différenciation et physiologie des lymphocytes T (U1020), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Alloimmunité-Autoimmunité-Transplantation (A2T), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Virologie et Immunologie Moléculaires, Université Francois Rabelais [Tours], Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'immunologie, AP-HP Hôpital universitaire Robert-Debré [Paris], Laboratoire de Biologie et de Pharmacologie Appliquée (LBPA), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC), Equipe 11, 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 médecine oncologique [Gustave Roussy], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), 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), 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 Gustave Roussy ( IGR ), Université Paris-Sud 11 - Faculté de médecine ( UP11 UFR Médecine ), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] ( DITEP ), Assistance Publique - Hôpitaux de Marseille ( APHM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital de la Conception [CHU - APHM] ( LA CONCEPTION ) -Centre National de la Recherche Scientifique ( CNRS ), 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 ), Hôpital de la Conception [CHU - APHM] ( LA CONCEPTION ), Microorganismes, Molécules Bioactives et Physiopathologie Intestinale ( LBM-E4 ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de rhumatologie, inflammation-immunopathologie- biothérapie [CHU Saint-Antoine] ( DHU i2B ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz, Institut Mutualiste de Montsouris ( IMM ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer ( LabEx LipSTIC ), Institut National de la Recherche Agronomique ( INRA ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Université Paris-Sud - Paris 11 ( UP11 ) -École pratique des hautes études ( EPHE ) -Institut Gustave Roussy ( IGR ) -Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ) -Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université de Franche-Comté ( UFC ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse ( U981 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Immunologie et Cancérologie Intégratives ( CRC - Inserm U1138 ), Centre de Recherche des Cordeliers ( CRC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ), Différenciation et physiologie des lymphocytes T ( U1020 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Necker Enfants-Malades ( INEM - UM 111 (UMR 8253 / U1151) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Alloimmunité-Autoimmunité-Transplantation ( A2T ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), 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 ), Laboratoire de Biologie et de Pharmacologie Appliquée ( LBPA ), École normale supérieure - Cachan ( ENS Cachan ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université de Franche-Comté ( UFC ), 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 ), 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 ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Service de rhumatologie [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Institut Bergonié [Bordeaux], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), University Medical Centre of the Johannes Gutenberg University Mainz, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Montpellier (UM), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Cachan (ENS Cachan), Medical Oncology, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École Pratique des Hautes Études (EPHE), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), and Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU)
Subjects: 0301 basic medicine, medicine.medical_treatment, Immunology, PDGFRA, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, medicine, Immunology and Allergy, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, neoplasms, Original Research, Tumor microenvironment, GiST, business.industry, Cancer, medicine.disease, digestive system diseases, 3. Good health, Immunosurveillance, 030104 developmental biology, Imatinib mesylate, Oncology, 030220 oncology & carcinogenesis, Cancer research, [SDV.IMM]Life Sciences [q-bio]/Immunology, business, Tyrosine kinase
Abstract: International audience; Despite effective targeted therapy acting on KIT and PDGFRA tyrosine kinases, gastrointestinal stromal tumors (GIST) escape treatment by acquiring mutations conveying resistance to imatinib mesylate (IM). Following the identification of NKp30-based immunosurveillance of GIST and the off-target effects of IM on NK cell functions, we investigated the predictive value of NKp30 isoforms and NKp30 soluble ligands in blood for the clinical response to IM. The relative expression and the proportions of NKp30 isoforms markedly impacted both event-free and overall survival, in two independent cohorts of metastatic GIST. Phenotypes based on disbalanced NKp30B/NKp30C ratio (Delta BClow) and low expression levels of NKp30A were identified in one third of patients with dismal prognosis across molecular subtypes. This Delta BClow blood phenotype was associated with a pro-inflammatory and immunosuppressive tumor microenvironment. In addition, detectable levels of the NKp30 ligand sB7-H6 predicted a worse prognosis in metastatic GIST. Soluble BAG6, an alternate ligand for NKp30 was associated with low NKp30 transcription and had additional predictive value in GIST patients with high NKp30 expression. Such GIST microenvironments could be rescued by therapy based on rIFN-alpha and anti-TRAIL mAb which reinstated innate immunity.
Published: 2017
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24. Immune Infiltrates Are Prognostic Factors in Localized Gastrointestinal Stromal Tumors

Author: Jean-François Emile, Frédéric Commo, Nadege Vimond, Guido Kroemer, Axel Le Cesne, Dirk Jäger, Sylvie Rusakiewicz, Philippe Terrier, Federico Garrido, Laurence Zitvogel, Alexander M.M. Eggermont, Jean-Yves Blay, Paule Opolon, Nicolas Isambert, Valérie Le Brun-Ly, Mélanie Desbois, Patrice Dubreuil, Vichnou Poirier-Colame, Isabelle Cremer, Nathalie Chaput, Michaela Semeraro, Niels Halama, Rosa Mendez, Loic Chaigneau, Kariman Chaba, Caroline Flament, Clara Locher, Ángel Concha, Sylvie Bonvalot, Jean-Michel Coindre, Matthieu Sarabi, and Anne Caignard
Subjects: Adult, Male, Cancer Research, Stromal cell, CD3 Complex, Gastrointestinal Stromal Tumors, T-Lymphocytes, Kaplan-Meier Estimate, Biology, Piperazines, Cohort Studies, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, 0302 clinical medicine, Immune system, medicine, Humans, Protein Kinase Inhibitors, neoplasms, Aged, 030304 developmental biology, Aged, 80 and over, 0303 health sciences, GiST, Natural Cytotoxicity Triggering Receptor 1, FOXP3, Cancer, Forkhead Transcription Factors, Middle Aged, Flow Cytometry, Prognosis, medicine.disease, Immunohistochemistry, CD56 Antigen, 3. Good health, Killer Cells, Natural, Immunosurveillance, Pyrimidines, Treatment Outcome, Imatinib mesylate, Oncology, 030220 oncology & carcinogenesis, Benzamides, Multivariate Analysis, Immunology, Imatinib Mesylate, Cancer research, Female, CD8
Abstract: Cancer immunosurveillance relies on effector/memory tumor-infiltrating CD8+ T cells with a T-helper cell 1 (TH1) profile. Evidence for a natural killer (NK) cell-based control of human malignancies is still largely missing. The KIT tyrosine kinase inhibitor imatinib mesylate markedly prolongs the survival of patients with gastrointestinal stromal tumors (GIST) by direct effects on tumor cells as well as by indirect immunostimulatory effects on T and NK cells. Here, we investigated the prognostic value of tumor-infiltrating lymphocytes (TIL) expressing CD3, Foxp3, or NKp46 (NCR1) in a cohort of patients with localized GIST. We found that CD3+ TIL were highly activated in GIST and were especially enriched in areas of the tumor that conserve class I MHC expression despite imatinib mesylate treatment. High densities of CD3+ TIL predicted progression-free survival (PFS) in multivariate analyses. Moreover, GIST were infiltrated by a homogeneous subset of cytokine-secreting CD56bright (NCAM1) NK cells that accumulated in tumor foci after imatinib mesylate treatment. The density of the NK infiltrate independently predicted PFS and added prognostic information to the Miettinen score, as well as to the KIT mutational status. NK and T lymphocytes preferentially distributed to distinct areas of tumor sections and probably contributed independently to GIST immunosurveillance. These findings encourage the prospective validation of immune biomarkers for optimal risk stratification of patients with GIST. Cancer Res; 73(12); 3499–510. ©2013 AACR.
Published: 2013
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25. The ratio of CD8

Author: Michaela, Semeraro, Julien, Adam, Gautier, Stoll, Emilie, Louvet, Kariman, Chaba, Vichnou, Poirier-Colame, Allan, Sauvat, Laura, Senovilla, Erika, Vacchelli, Norma, Bloy, Juliette, Humeau, Aitziber, Buque, Oliver, Kepp, Laurence, Zitvogel, Fabrice, André, Marie-Christine, Mathieu, Suzette, Delaloge, and Guido, Kroemer
Subjects: Original Research
Abstract: In a series of 248 tumor samples obtained from image-guided biopsies from patients diagnosed with ductal carcinoma in situ of the breast, we attempted to identify biomarkers that predict microinfiltration at definitive surgery or relapse during follow-up. For this, we used immunohistochemical methods, followed by automated image analyses, to measure the mean diameter of nuclei (which correlates with ploidy), the phosphorylation of eukaryotic initiation factor 2α (eIF2α, which reflects endoplasmic reticulum stress) as well as the density and ratio of CD8+ cytotoxic T lymphocytes and FOXP3+ regulatory T cells. The median nuclear diameter of malignant cells correlated with eIF2α phosphorylation (in cancerous tissue), which in turn correlated with the density of the CD8+ infiltrate and the CD8+/FOXP3 ratio (both in cancerous and the adjacent non-cancerous parenchyma). Neither microinfiltration nor lymph node involvement was associated with the probability of relapse. Both correlated positively with the CD8+/FOXP3 ratio in the malignant area. In contrast, relapse was associated with a paucity of the CD8+ infiltrate as well as an unfavorable CD8+/FOXP3 ratio, both in malignant and non-malignant parenchyma. The combined analysis of the CD8+/FOXP3 ratio in cancerous and non-cancerous tissues revealed a significant impact of their interaction on the probability of relapse, but not on the presence of microinfiltration or lymph node metastasis. Altogether, these results support the idea of an immunosurveillance system that determines the risk of relapse in ductal carcinoma in situ of the breast.
Published: 2016

26. Immunohistochemical detection of cytoplasmic LC3 puncta in human cancer specimens

Author: Mickaël Michaud, Vichnou Poirier-Colame, Mathias T. Rosenfeldt, Abdul Qader Sukkurwala, Sandy Adjemian, Lorenzo Galluzzi, Sylvain Ladoire, Felipe Andreiuolo, Kevin M. Ryan, Isabelle Martins, Guido Kroemer, Eileen White, Laurence Zitvogel, and Kariman Chaba
Subjects: Cytoplasm, Pathology, medicine.medical_specialty, ATG5, Cell, Biology, Mice, Cell Line, Tumor, Neoplasms, medicine, Animals, Humans, Molecular Biology, Gene knockdown, Tissue microarray, Staining and Labeling, Cancer, Cell Biology, medicine.disease, Immunohistochemistry, Basic Research Paper, Staining, Cell biology, Mice, Inbred C57BL, Disease Models, Animal, medicine.anatomical_structure, Tissue Array Analysis, Cell culture, embryonic structures, biological phenomena, cell phenomena, and immunity, Microtubule-Associated Proteins
Abstract: Autophagy is an evolutionarily conserved catabolic process that involves the entrapment of cytoplasmic components within characteristic vesicles for their delivery to and degradation within lysosomes. Alterations in autophagic signaling are found in several human diseases including cancer. Here, we describe a validated immunohistochemical protocol for the detection of LC3 puncta in human formalin-fixed, paraffin-embedded cancer specimens that can also be applied to mouse tissues. In response to systemic chemotherapy, autophagy-competent mouse tumors exhibited LC3 puncta, which did not appear in mouse cancers that had been rendered autophagy-deficient by the knockdown of Atg5 or Atg7. As compared with normal tissues, LC3 staining was moderately to highly elevated in the large majority of human cancers studied, albeit tumors of the same histological type tended to be highly heterogeneous in the number and intensity of LC3 puncta per cell. Moreover, tumor-infiltrating immune cells often were highly positive for LC3. Altogether, this protocol for LC3 staining appears suitable for the specific detection of LC3 puncta in human specimens, including tissue microarrays. We surmise that this technique can be employed for retrospective or prospective studies involving large series of human tumor samples.
Published: 2012
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27. Biomarkers of immunogenic stress in metastases from melanoma patients: Correlations with the immune infiltrate

Author: Jochen T. Schaefer, Kariman Chaba, Sylvain Ladoire, David Enot, Laurence Zitvogel, Gulsun Erdag, Vichnou Poirier-Colame, Donna H. Deacon, François Ghiringhelli, Guido Kroemer, Craig L. Slingluff, Laura Senovilla, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, 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), Immunologie et Cancérologie Intégratives (CRC - Inserm U1138), Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Lipides - Nutrition - Cancer (U866) (LNC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Department of Surgery, Division of Surgical Oncology-University of Virginia School of Medicine, Department of pathology [Virginia], University of Virginia [Charlottesville], 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), Karolinska Institutet [Stockholm], Service de biologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), University of Virginia, Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), 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 ), Immunologie et Cancérologie Intégratives ( CRC - Inserm U1138 ), Centre de Recherche des Cordeliers ( CRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre d'Investigation Clinique en Biotherapie des cancers ( CIC 1428 , CBT 507 ), Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: 0301 basic medicine, Hmgb1 Expression, CD3, Immunology, T-Cells, chemical and pharmacologic phenomena, Immunogenic Cell Death, [SDV.CAN]Life Sciences [q-bio]/Cancer, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Immune system, medicine, Autophagy, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Immunology and Allergy, Cytotoxic T cell, Cell-Death, Breast-Cancer, Melanoma, Lc3b Puncta, Original Research, Hmgb1, biology, Anticancer Chemotherapy, Immune Infiltrates, Immunosurveillance, FOXP3, medicine.disease, 3. Good health, 030104 developmental biology, Oncology, Cancer research, biology.protein, Lc3, Immunogenic cell death, [SDV.IMM]Life Sciences [q-bio]/Immunology, Mechanism, Therapy, Calreticulin, CD8
Abstract: International audience; Melanoma is known to be under latent immunosurveillance. Here, we studied four biomarkers of immunogenic cell stress and death (microtubule-associated proteins 1A/1B light chain 3B (MAP-LC3B, best known as LC3B)-positive puncta in the cytoplasm as a sign of autophagy; presence of nuclear HMGB1; phosphorylation of eIF2 alpha; increase in ploidy) in melanoma cells, in tissue microarrays (TMA) from metastases from 147 melanoma patients. These biomarkers of immunogenicity were correlated with the density of immune cells infiltrating the metastases and expressing CD3, CD4(+), CD8(+), CD20, CD45, CD56, CD138, CD163, DC-LAMP or FOXP3. LC3B puncta positively correlated with the infiltration of metastases by CD163(+) macrophages, while expression of HMGB1 correlated with infiltration by FOXP3(+) regulatory T cells and CD56(+) lymphocytes. eIF2 alpha phosphorylation was associated with an augmentation of nuclear diameters, reflecting an increase in ploidy. Interestingly, therapeutic vaccination led to a reduction of eIF2 alpha phosphorylation suggestive of immunoselection against cells bearing this sign of endoplasmic reticulum (ER) stress. None of the stress/death-related biomarkers had a significant prognostic impact, contrasting with the major prognostic effect of the ratio of cytotoxic T lymphocytes (CTL) over immunosuppressive FOXP3(+) and CD163(+) cells. Altogether, these results support the idea of a mutual dialog between, on one hand, melanoma cells with their cell-intrinsic stress pathways and, on the other hand, immune effectors. Future work is required to understand the detailed mechanisms of this interaction.Keywords
Published: 2016
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28. The presence of LC3B puncta and HMGB1 expression in malignant cells correlate with the immune infiltrate in breast cancer

Author: Laura Senovilla, Marie Laure Poillot, Guido Kroemer, Marie Chaix, Patrick Arveux, Fabrice Andre, Laurent Arnould, Vichnou Poirier-Colame, Laurence Zitvogel, Sylvain Ladoire, David Enot, Suzette Delaloge, François Ghiringhelli, Frédérique Penault-Llorca, Kariman Chaba, Michaela Semeraro, Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut Gustave Roussy (IGR), Immunologie et Cancérologie Intégratives (CRC - Inserm U1138), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe de recherche sur les traitements individualisés des cancers (ERTICa), Université d'Auvergne - Clermont-Ferrand I (UdA), Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Département de médecine oncologique [Gustave Roussy], Karolinska University Hospital [Stockholm], Service de biologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie des tumeurs et immunothérapie ( UMR 1015 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Institut Gustave Roussy ( IGR ), Immunologie et Cancérologie Intégratives ( CRC - Inserm U1138 ), Centre de Recherche des Cordeliers ( CRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), 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 ), Equipe de recherche sur les traitements individualisés des cancers ( ERTICa ), Université d'Auvergne - Clermont-Ferrand I ( UdA ), Centre d'épidémiologie des populations ( CEP ), Université de Bourgogne ( UB ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Assistance publique - Hôpitaux de Paris (AP-HP), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE)
Subjects: 0301 basic medicine, Pathological Complete Response, 0302 clinical medicine, Pathology, Cytotoxic T cell, Lymphocytes, HMGB1 Protein, FOXP3, Forkhead Transcription Factors, Mammary Tumorigenesis, 3. Good health, Immunosurveillance, Death, 030220 oncology & carcinogenesis, Female, Beclin-1, Microtubule-Associated Proteins, Infiltration (medical), Histology, Predictive-Value, Breast Neoplasms, chemical and pharmacologic phenomena, Cd8, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Prognostic, 03 medical and health sciences, Immune system, Breast Cancer, medicine, Autophagy, Humans, Prognostic Value, Treg Cells, Molecular Biology, Hmgb1, Anticancer Chemotherapy, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, Macrophages, Neoadjuvant Chemotherapy, Cell Biology, medicine.disease, 030104 developmental biology, Tumor progression, Cancer cell, Immunology, Cancer research, Lc3, Clinical Research Paper, CD8, T-Lymphocytes, Cytotoxic
Abstract: International audience; Several cell-intrinsic alterations have poor prognostic features in human breast cancer, as exemplified by the absence of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 )-positive puncta in the cytoplasm (which indicates reduced autophagic flux) or the loss of nuclear HMGB1 expression by malignant cells. It is well established that breast cancer is under strong immunosurveillance, as reflected by the fact that scarce infiltration of the malignant lesion by CD8(+) cytotoxic T lymphocytes or comparatively dense infiltration by immunosuppressive cell types (such as FOXP3(+) regulatory T cells or CD68(+) tumor-associated macrophages), resulting in low CD8(+):FOXP3(+) or CD8(+):CD68(+) ratios, has a negative prognostic impact. Here, we reveal the surprising finding that cell-intrinsic features may influence the composition of the immune infiltrate in human breast cancer. Thus, the absence of LC3B puncta is correlated with intratumoral (but not peritumoral) infiltration by fewer CD8(+) cells and more FOXP3(+) or CD68(+) cells, resulting in a major drop in the CD8(+):FOXP3(+) or CD8(+):CD68(+) ratios. Moreover, absence of HMGB1 expression in nuclei correlated with a general drop in all immune effectors, in particular FOXP3(+) and CD68(+) cells, both within the tumor and close to it. Combined analysis of LC3B puncta and HMGB1 expression allowed for improved stratification of patients with respect to the characteristics of their immune infiltrate as well as overall and metastasis-free survival. It can be speculated that blocked autophagy in, or HMGB1 loss from, cancer cells may favor tumor progression due to their negative impact on anticancer immunosurveillance.
Published: 2016
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29. Morphometric analysis of immunoselection against hyperploid cancer cells

Author: Norma, Bloy, Allan, Sauvat, Kariman, Chaba, Aitziber, Buqué, Juliette, Humeau, José Manuel, Bravo-San Pedro, Jack, Bui, Oliver, Kepp, Guido, Kroemer, and Laura, Senovilla
Subjects: Cell Nucleus, Mice, Knockout, morphometric analysis, Eukaryotic Initiation Factor-2, Immunoblotting, ER stressi, ploidy, Neoplasms, Experimental, Endoplasmic Reticulum Stress, Flow Cytometry, Diploidy, Immunohistochemistry, mmunoselection, Mice, Inbred C57BL, Polyploidy, Microscopy, Fluorescence, Cell Line, Tumor, Animals, Phosphorylation, Research Paper
Abstract: An at least transient increase of ploidy, usually by whole genome duplication, is a frequent event in oncogenesis, explaining the cytogenetic features of at least 40% of solid cancers. Here, we show that fibrosarcomas induced by the carcinogen methylcholanthrene (MCA) are distinct with respect to their ploidy status when they arise in immunocompetent wild type versus severely immunodeficient Rag2−/−γc−/− mice. MCA-induced fibrosarcomas are particularly hyperploid if they develop in an immunodeficient setting, correlating with higher DNA content, increased nuclear surface, as well as hyperphosphorylation of eukaryotic initiation factor 2` (eIF2`), a biomarker indicating endoplasmic reticulum (ER) stress. Upon transfer of such cells into wild type mice, such hyperploid, ER-stressed cells (that originated in Rag2−/−γc−/− mice) fail to proliferate and actually induce a protective anticancer immune response. In contrast, such cells do form tumors in Rag2−/−γc−/− recipients (which lack T, B and NK cells) as well as in Rag2−/− recipients (which only lack T and B lymphocytes) and conserve their hyperploidy as well as eIF2` hyperphosphorylation. To measure these parameters, we developed a morphometric analysis tool that is applicable to immunohistochemistry of formaldehyde-fixed, paraffin-embedded tissues. This software automatically identifies and quantifies the surface of nuclei and determines the intensity of eIF2` phosphorylation within a perinuclear region of interest. Comparative analyses performed on cultured cells and tissue sections validated the accuracy of this method, which can be used to investigate ploidy and ER stress in cancers in situ.
Published: 2015

30. Chemotherapy-induced antitumor immunity requires formyl peptide receptor 1

Author: Guido Kroemer, Oliver Kepp, Fabrice Andre, Patrick Günther, José Manuel Bravo-San Pedro, Thomas Ulas, Sandy Adjemian, Elisa E. Baracco, Adele De Ninno, Gwenola Manic, Luca Businaro, Ilio Vitale, Valeria Lucarini, Monica Lucattelli, Federico Pietrocola, Suzette Delaloge, Laurence Zitvogel, Yuting Ma, Joachim L. Schultze, Michaela Semeraro, Giovanna Schiavoni, Celine Lefebvre, Heng Yang, Kariman Chaba, Lionel Apetoh, Antonella Sistigu, Sylvain Ladoire, Gautier Stoll, Christophe Borg, David Enot, Valérie Boige, Michel Ducreux, Francesca Castoldi, Francesca Peschiaroli, Fabrizio Mattei, Sylvie Rusakiewicz, Erika Vacchelli, Cécile Delarasse, Michele Signore, Annamaria Gerardino, Claire Mulot, and Pierre Laurent-Puig
Subjects: Anthracycline, Colorectal cancer, medicine.medical_treatment, T-Lymphocytes, Breast Neoplasms, microfluidic chip, chemotherapy, Polymorphism, Single Nucleotide, Formyl peptide receptor 1, immune response, Mice, Immune system, Immunity, Cell Line, Tumor, Neoplasms, medicine, Leukocytes, Animals, Humans, Anthracyclines, Alleles, Annexin A1, Chemotherapy, Multidisciplinary, business.industry, Dendritic Cells, medicine.disease, Receptors, Formyl Peptide, Immunity, Innate, Chemotherapy, Adjuvant, Cancer cell, Immunology, Cancer research, Female, business, Colorectal Neoplasms, Adjuvant, FPR1 microfluidic
Abstract: How dying tumor cells get noticed Besides killing tumor cells directly, some chemotherapies, such as anthracyclines, also activate the immune system to kill tumors. Vacchelli et al. discovered that in mice, anthracycline-induced antitumor immunity requires immune cells to express the protein formyl peptide receptor 1 (FPR1). Dendritic cells (DCs) near tumors expressed especially high amounts of FPR1. DCs normally capture fragments of dying tumor cells and use them to activate nearby T cells to kill tumors, but DCs lacking FPR1 failed to do this effectively. Individuals with breast or colon cancer expressing a variant of FPR1 and treated with anthracyclines showed poor metastasis-free and overall survival. Thus, FPR1 may affect anti-tumor immunity in people, too. Science , this issue p. 972
Published: 2015
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31. Cancer cell–autonomous contribution of type I interferon signaling to the efficacy of chemotherapy

Author: Aicha Goubar, Julien Adam, Joanna Cyrta, Kariman Chaba, Mireia Niso-Santano, Valentina La Sorsa, Laurence Zitvogel, Christina Pfirschke, Guido Kroemer, Gilles Uzé, Oliver Kepp, Magali Lacroix-Triki, Francesca Urbani, Antonella Sistigu, Elisa E. Baracco, Suzette Delaloge, Sylvain Ladoire, David Enot, Camilla Engblom, Marco Bianchi, Laurent Arnould, Virginie Quidville, Mauro Delorenzi, Enrico Proietti, Melvyn T. Chow, Laetitia Aymeric, Fabrice Andre, Giovanna Ziccheddu, Joachim L. Schultze, Alexander M.M. Eggermont, Thomas Tüting, Laetitia Fend, Mark J. Smyth, Catarina Remédios, Takahiro Yamazaki, Robert D. Schreiber, Laura Bracci, Erika Vacchelli, Rosa Conforti, Ilio Vitale, Paola Sestili, Mikael J. Pittet, Marie Charlotte Dessoliers, Filippo Belardelli, Vichnou Poirier-Colame, Frédérique Penault-Llorca, Jean Philippe Spano, Lajos Pusztai, Xavier Préville, Dalil Hannani, Yuting Ma, National Cancer Institute Regina Elena [Rome, Italy], 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), Apoptose, cancer et immunité (Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie et Cancérologie Intégratives (CRC - Inserm U1138), Centre de Recherche des Cordeliers (CRC), Institut Gustave Roussy (IGR), Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Département de biologie et pathologie médicales [Gustave Roussy], Apoptose, cancer et immunité (U848), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), Institut Gustave Roussy (IGR)-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)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Life and Medical Sciences Institute for Genomics and Immunoregulation, Universität Bonn = University of Bonn, Dept. of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità (ISS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of Breast Medical Oncology [Houston], The University of Texas M.D. Anderson Cancer Center [Houston], Pathologie mammaire, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Département de Biologie et pathologie des tumeurs [Centre Georges-François Leclerc], UNICANCER-UNICANCER, Harvard Medical School [Boston] (HMS), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Department of Cell Biology and Neurosciences, Université Paris-Sud - Paris 11 (UP11), Sistigu, A, Yamazaki, T, Vacchelli, E, Chaba, K, Enot, Dp, Adam, J, Vitale, I, Goubar, A, Baracco, Ee, Remédios, C, Fend, L, Hannani, D, Aymeric, L, Ma, Y, Niso Santano, M, Kepp, O, Schultze, Jl, Tüting, T, Belardelli, F, Bracci, L, La Sorsa, V, Ziccheddu, G, Sestili, P, Urbani, F, Delorenzi, M, Lacroix Triki, M, Quidville, V, Conforti, R, Spano, Jp, Pusztai, L, Poirier Colame, V, Delaloge, S, Penault Llorca, F, Ladoire, S, Arnould, L, Cyrta, J, Dessoliers, Mc, Eggermont, A, Bianchi, MARCO EMILIO, Pittet, M, Engblom, C, Pfirschke, C, Préville, X, Uzè, G, Schreiber, Rd, Chow, Mt, Smyth, Mj, Proietti, E, André, F, Kroemer, G, Zitvogel, L., Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE), University of Bonn, Istituto Superiore di Sanità, Service d'Oncologie médicale [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Istituto Superiore di Sanita', and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Myxovirus Resistance Proteins, Messenger, Receptor, Interferon alpha-beta, Inbred C57BL, chemotherapy, Interferon alpha-beta, Mice, Interferon, Receptors, Anthracyclines, Neoplasm Metastasis, RIG-I, Pattern recognition receptor, Adaptor Proteins, General Medicine, Neoadjuvant Therapy, 3. Good health, Gene Expression Regulation, Neoplastic, Treatment Outcome, Receptors, Pattern Recognition, Interferon Type I, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Immunocompetence, medicine.drug, Receptor, Signal Transduction, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Pattern Recognition, Settore BIO/09, General Biochemistry, Genetics and Molecular Biology, Paracrine signalling, Immune system, medicine, CXCL10, Animals, Humans, cancer, RNA, Messenger, Autocrine signalling, Neoplastic, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Toll-Like Receptor 3, Mice, Inbred C57BL, Vesicular Transport, Chemokine CXCL10, Adaptor Proteins, Vesicular Transport, Gene Expression Regulation, Doxorubicin, Immunology, TLR3, RNA
Abstract: International audience; The immune system is routinely confronted with cell death resulting from the physiological turnover of renewable tissues, as well as from pathological insults of several types. We hypothesize the existence of a mechanism that allows the immune system to discriminate between physiological and pathological instances of cell death, but the factors that determine whether cellular demise is perceived as a neutral, tolerogenic or immunogenic event remain unclear 1. Infectious insults are accompanied by so-called microbe-associated molecular patterns (MAMPs), i.e., viral or bacterial products that activate immune cells through a panel of pattern-recognition receptors (PRRs) 2. Moreover, intracellular pathogens generally trigger adaptive mechanisms aimed toward the re-establishment of homeosta-sis, including the unfolded protein response (UPR) and autophagy 3,4. In mammals, MAMPs coupled to the activation of stress responses Some of the anti-neoplastic effects of anthracyclines in mice originate from the induction of innate and T cell-mediated anticancer immune responses. Here we demonstrate that anthracyclines stimulate the rapid production of type I interferons (IFNs) by malignant cells after activation of the endosomal pattern recognition receptor Toll-like receptor 3 (TLR3). By binding to IFN- and IFN- receptors (IFNARs) on neoplastic cells, type I IFNs trigger autocrine and paracrine circuitries that result in the release of chemokine (C-X-C motif) ligand 10 (CXCL10). Tumors lacking Tlr3 or Ifnar failed to respond to chemotherapy unless type I IFN or Cxcl10, respectively, was artificially supplied. Moreover, a type I IFN-related signature predicted clinical responses to anthracycline-based chemotherapy in several independent cohorts of patients with breast carcinoma characterized by poor prognosis. Our data suggest that anthracycline-mediated immune responses mimic those induced by viral pathogens. We surmise that such 'viral mimicry' constitutes a hallmark of successful chemotherapy. npg
Published: 2014
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32. Coffee induces autophagy in vivo

Author: Erika Vacchelli, Guillermo Mariño, Federico Pietrocola, Shoaib Ahmad Malik, Laura Senovilla, Kariman Chaba, Frank Madeo, Guido Kroemer, Mireia Niso-Santano, Maria Chiara Maiuri, Pietrocola, F, Malik, Sa, Mariño, G, Vacchelli, E, Senovilla, L, Chaba, K, Niso Santano, M, Maiuri, MARIA CHIARA, Madeo, F, and Kroemer, G.
Subjects: Genetically modified mouse, mTORC1, Mechanistic Target of Rapamycin Complex 1, Biology, Coffee, Cell Cycle News & Views, Sequestosome 1, In vivo, Phagosomes, Report, Autophagy, Animals, Muscle, Skeletal, education, Molecular Biology, Adaptor Proteins, Signal Transducing, education.field_of_study, Myocardium, TOR Serine-Threonine Kinases, Acetylation, Cell Biology, Fusion protein, Cell biology, Mice, Inbred C57BL, Liver, Multiprotein Complexes, Phosphorylation, Female, Transcription Factor TFIIH, Transcription Factors, Developmental Biology
Abstract: Epidemiological studies and clinical trials revealed that chronic consumption coffee is associated with the inhibition of several metabolic diseases as well as reduction in overall and cause-specific mortality. We show that both natural and decaffeinated brands of coffee similarly rapidly trigger autophagy in mice. One to 4 h after coffee consumption, we observed an increase in autophagic flux in all investigated organs (liver, muscle, heart) in vivo, as indicated by the increased lipidation of LC3B and the reduction of the abundance of the autophagic substrate sequestosome 1 (p62/SQSTM1). These changes were accompanied by the inhibition of the enzymatic activity of mammalian target of rapamycin complex 1 (mTORC1), leading to the reduced phosphorylation of p70(S6K), as well as by the global deacetylation of cellular proteins detectable by immunoblot. Immunohistochemical analyses of transgenic mice expressing a GFP-LC3B fusion protein confirmed the coffee-induced relocation of LC3B to autophagosomes, as well as general protein deacetylation. Altogether, these results indicate that coffee triggers 2 phenomena that are also induced by nutrient depletion, namely a reduction of protein acetylation coupled to an increase in autophagy. We speculate that polyphenols contained in coffee promote health by stimulating autophagy.
Published: 2014

33. The presence of LC3B puncta and HMGB1 expression in malignant cells correlate with the immune infiltrate in breast cancer

Author: Sylvain Ladoire, David Enot, Laura Senovilla, François Ghiringhelli, Vichnou Poirier-Colame, Kariman Chaba, Michaela Semeraro, Marie Chaix, Frédérique Penault-Llorca, Laurent Arnould, Marie Laure Poillot, Patrick Arveux, Suzette Delaloge, Fabrice Andre, Laurence Zitvogel, Guido Kroemer, Sylvain Ladoire, David Enot, Laura Senovilla, François Ghiringhelli, Vichnou Poirier-Colame, Kariman Chaba, Michaela Semeraro, Marie Chaix, Frédérique Penault-Llorca, Laurent Arnould, Marie Laure Poillot, Patrick Arveux, Suzette Delaloge, Fabrice Andre, Laurence Zitvogel, and Guido Kroemer
Abstract: Several cell-intrinsic alterations have poor prognostic features in human breast cancer, as exemplified by the absence of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 β)-positive puncta in the cytoplasm (which indicates reduced autophagic flux) or the loss of nuclear HMGB1 expression by malignant cells. It is well established that breast cancer is under strong immunosurveillance, as reflected by the fact that scarce infiltration of the malignant lesion by CD8+ cytotoxic T lymphocytes or comparatively dense infiltration by immunosuppressive cell types (such as FOXP3+ regulatory T cells or CD68+ tumor-associated macrophages), resulting in low CD8+:FOXP3+ or CD8+:CD68+ ratios, has a negative prognostic impact. Here, we reveal the surprising finding that cell-intrinsic features may influence the composition of the immune infiltrate in human breast cancer. Thus, the absence of LC3B puncta is correlated with intratumoral (but not peritumoral) infiltration by fewer CD8+ cells and more FOXP3+ or CD68+ cells, resulting in a major drop in the CD8+:FOXP3+ or CD8+:CD68+ ratios. Moreover, absence of HMGB1 expression in nuclei correlated with a general drop in all immune effectors, in particular FOXP3+ and CD68+ cells, both within the tumor and close to it. Combined analysis of LC3B puncta and HMGB1 expression allowed for improved stratification of patients with respect to the characteristics of their immune infiltrate as well as overall and metastasis-free survival. It can be speculated that blocked autophagy in, or HMGB1 loss from, cancer cells may favor tumor progression due to their negative impact on anticancer immunosurveillance.
Published: 2016
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34. Combined evaluation of LC3B puncta and HMGB1 expression predicts residual risk of relapse after adjuvant chemotherapy in breast cancer

Author: Sylvain Ladoire, Frédérique Penault-Llorca, Laura Senovilla, Cécile Dalban, David Enot, Clara Locher, Nicole Prada, Vichnou Poirier-Colame, Kariman Chaba, Laurent Arnould, François Ghiringhelli, Pierre Fumoleau, Marc Spielmann, Suzette Delaloge, Marie Laure Poillot, Patrick Arveux, Aicha Goubar, Fabrice Andre, Laurence Zitvogel, Guido Kroemer, Sylvain Ladoire, Frédérique Penault-Llorca, Laura Senovilla, Cécile Dalban, David Enot, Clara Locher, Nicole Prada, Vichnou Poirier-Colame, Kariman Chaba, Laurent Arnould, François Ghiringhelli, Pierre Fumoleau, Marc Spielmann, Suzette Delaloge, Marie Laure Poillot, Patrick Arveux, Aicha Goubar, Fabrice Andre, Laurence Zitvogel, and Guido Kroemer
Published: 2016
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35. Regulation of CD4+NKG2D+ Th1 Cells in Patients with Metastatic Melanoma Treated with Sorafenib: Role of IL-15Rα and NKG2D Triggering

Author: Sylvie Rusakiewicz, Sophie Caillat-Zucman, Christine Mateus, Yannick Jacques, Caroline Flament, Caroline Robert, Vichnou Poirier-Colame, Nathalie Chaput, Danila Valmori, Philippe Dessen, Philippe Vielh, Erwan Mortier, Nicolas Jacquelot, Maha Ayyoub, Camillo Porta, Laurence Zitvogel, Alexander M.M. Eggermont, Ana I. Romero, Anne Auperin, Anne Caignard, Meriem Messaoudene, Kariman Chaba, Institut Gustave Roussy (IGR), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Laboratoire de recherche translationnelle, Direction de la recherche [Gustave Roussy], Hématopoïèse normale et pathologique (U1170 Inserm), Stabilité Génétique et Oncogenèse (UMR 8200), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), IRCCS San Matteo Hospital Foundation & University of Pavia, Service de dermatologie, Département de médecine oncologique [Gustave Roussy], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Université Paris-Sud - Paris 11 (UP11), This work was supported by Schering-Plough legacy, Bayer Schering Pharma, Institut National du Cancer INCa, ANR, Ligue contre le cancer (équipe labellisée de LZ) and INFLACARE EU grant, ISREC Foundation, SIRIC SOCRATES, LABEX OncoImmunology, PACRI network. S. Rusakiewicz and V. Poirier-Colame were supported by the Fondation pour la Recherche Medicale (FRM) and the Fondation de France respectively. A.I. Romero was supported by the Swedish Research Council., Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Università degli Studi di Pavia = University of Pavia (UNIPV), and Mortier, Erwan
Subjects: Male, Cancer Research, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Ligands, 0302 clinical medicine, Enzymes -- Regulation, Vemurafenib, Melanoma, Interleukin-15, 0303 health sciences, Interleukin, Middle Aged, Sorafenib, 3. Good health, [SDV] Life Sciences [q-bio], Oncology, NK Cell Lectin-Like Receptor Subfamily K, 030220 oncology & carcinogenesis, CD4 Antigens, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, CD4 antigen, Adjuvant, medicine.drug, Adult, Niacinamide, [SDV.IMM] Life Sciences [q-bio]/Immunology, Killer cells, Cells -- Growth, chemical and pharmacologic phenomena, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Growth Processes, Young Adult, 03 medical and health sciences, Immune system, Interleukin-15 Receptor alpha Subunit, Antigen, [SDV.CAN] Life Sciences [q-bio]/Cancer, Th1 cells, medicine, Humans, Antigens, Aged, 030304 developmental biology, business.industry, Phenylurea Compounds, Th1 Cells, medicine.disease, NKG2D, Cancer research, business
Abstract: Beyond cancer-cell intrinsic factors, the immune status of the host has a prognostic impact on patients with cancer and influences the effects of conventional chemotherapies. Metastatic melanoma is intrinsically immunogenic, thereby facilitating the search for immune biomarkers of clinical responses to cytotoxic agents. Here, we show that a multi-tyrosine kinase inhibitor, sorafenib, upregulates interleukin (IL)-15Rα in vitro and in vivo in patients with melanoma, and in conjunction with natural killer (NK) group 2D (NKG2D) ligands, contributes to the Th1 polarization and accumulation of peripheral CD4+NKG2D+ T cells. Hence, the increase of blood CD4+NKG2D+ T cells after two cycles of sorafenib (combined with temozolomide) was associated with prolonged survival in a prospective phase I/II trial enrolling 63 patients with metastatic melanoma who did not receive vemurafenib nor immune checkpoint-blocking antibodies. In contrast, in metastatic melanoma patients treated with classical treatment modalities, this CD4+NKG2D+ subset failed to correlate with prognosis. These findings indicate that sorafenib may be used as an "adjuvant" molecule capable of inducing or restoring IL-15Rα/IL-15 in tumors expressing MHCclass I-related chain A/B (MICA/B) and on circulating monocytes of responding patients, hereby contributing to the bioactivity of NKG2D+ Th1 cells., peer-reviewed
Published: 2014
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36. The ratio of CD8+/FOXP3 T lymphocytes infiltrating breast tissues predicts the relapse of ductal carcinoma in situ

Author: Fabrice Andre, Guido Kroemer, Gautier Stoll, Aitziber Buqué, Juliette Humeau, Oliver Kepp, Michaela Semeraro, Laura Senovilla, Suzette Delaloge, Vichnou Poirier-Colame, Laurence Zitvogel, Kariman Chaba, Julien Adam, Allan Sauvat, Norma Bloy, Erika Vacchelli, Emilie Louvet, and Marie-Christine Mathieu
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, Immunology, FOXP3, Biology, Ductal carcinoma, Immunosurveillance, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Parenchyma, medicine, Immunology and Allergy, Immunohistochemistry, Cytotoxic T cell, Lymph node, CD8
Abstract: In a series of 248 tumor samples obtained from image-guided biopsies from patients diagnosed with ductal carcinoma in situ of the breast, we attempted to identify biomarkers that predict microinfiltration at definitive surgery or relapse during follow-up. For this, we used immunohistochemical methods, followed by automated image analyses, to measure the mean diameter of nuclei (which correlates with ploidy), the phosphorylation of eukaryotic initiation factor 2α (eIF2α, which reflects endoplasmic reticulum stress) as well as the density and ratio of CD8+ cytotoxic T lymphocytes and FOXP3+ regulatory T cells. The median nuclear diameter of malignant cells correlated with eIF2α phosphorylation (in cancerous tissue), which in turn correlated with the density of the CD8+ infiltrate and the CD8+/FOXP3 ratio (both in cancerous and the adjacent non-cancerous parenchyma). Neither microinfiltration nor lymph node involvement was associated with the probability of relapse. Both correlated positively with the CD8+/FOXP3 ratio in the malignant area. In contrast, relapse was associated with a paucity of the CD8+ infiltrate as well as an unfavorable CD8+/FOXP3 ratio, both in malignant and non-malignant parenchyma. The combined analysis of the CD8+/FOXP3 ratio in cancerous and non-cancerous tissues revealed a significant impact of their interaction on the probability of relapse, but not on the presence of microinfiltration or lymph node metastasis. Altogether, these results support the idea of an immunosurveillance system that determines the risk of relapse in ductal carcinoma in situ of the breast.
Published: 2016
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37. Combined evaluation of LC3B puncta and HMGB1 expression predicts residual risk of relapse after adjuvant chemotherapy in breast cancer

Author: Sylvain Ladoire, Frédérique Penault-Llorca, Laura Senovilla, Cécile Dalban, David Enot, Clara Locher, Nicole Prada, Vichnou Poirier-Colame, Kariman Chaba, Laurent Arnould, François Ghiringhelli, Pierre Fumoleau, Marc Spielmann, Suzette Delaloge, Marie Laure Poillot, Patrick Arveux, Aicha Goubar, Fabrice Andre, Laurence Zitvogel, Guido Kroemer, Sylvain Ladoire, Frédérique Penault-Llorca, Laura Senovilla, Cécile Dalban, David Enot, Clara Locher, Nicole Prada, Vichnou Poirier-Colame, Kariman Chaba, Laurent Arnould, François Ghiringhelli, Pierre Fumoleau, Marc Spielmann, Suzette Delaloge, Marie Laure Poillot, Patrick Arveux, Aicha Goubar, Fabrice Andre, Laurence Zitvogel, and Guido Kroemer
Published: 2015
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38. Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors

Author: Frédéric Commo, Sylvie Rusakiewicz, Jean Franãois Emile, Caroline Flament, Jean-Yves Blay, Nicolas Ibrahim, Véronique Minard-Colin, Saadia Kerdine-Römer, Philippe Terrier, Jacques A. Nunès, Cédric Ménard, Pascale Paul, Benedita Rocha, Laurence Zitvogel, Kariman Chaba, Alessandro Moretta, Dominique Valteau-Couanet, Cristina Bottino, Javier Celis Gutierrez, Luc Lyonnet, A. Lecesne, Nathalie Chaput, Stephan Roux, Hélène Authier, Jean Michel Coindre, Matthieu Sarabi, Pascal Rihet, Véronique Baud, Nicolas F. Delahaye, Laetitia Peaudecerf, Isabelle Martins, Sylvie Bonvalot, Jan Tavernier, Eric Vivier, Nicolas Isambert, Michaela Semeraro, Isabelle Cremer, Marc Pallardy, Paule Opolon, Vichnou Poirier-Colame, Guido Kroemer, 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), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-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), 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), Service de Chirurgie, Assistance Publique - Hôpitaux de Marseille (APHM)-Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), Department of Immunology, Duke University Medical Center, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), School of Medicine, Université Paris-Sud - Paris 11 (UP11), Recepteurs et Signalisation des Interleukines (U749), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de Pédiatrie, Institut Gustave Roussy (IGR), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d'anatomie pathologique [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], Département de biologie et pathologie médicales [Gustave Roussy], Vectorologie et transfert de gènes (VTG / UMR8121), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Università di Genova, Dipartimento di Medicina Sperimentale, Universita degli studi di Genova, Biochemistry, Ghent University [Belgium] (UGENT), Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques (IP-TPT), Service de Santé des Armées-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD), Département de pathologie, Institut Bergonié - CRLCC Bordeaux, Département de Médecine Nucléaire, Centre Léon Bérard [Lyon], Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Laboratory of Human Genetics of Infectious Diseases, Apoptose, cancer et immunité (U848), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Pôle de biologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), 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 ), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Jacques Monod ( IJM ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), 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 ), Assistance Publique - Hôpitaux de Marseille ( APHM ) -Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] ( LA CONCEPTION ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), Université Paris-Sud - Paris 11 ( UP11 ), Recepteurs et Signalisation des Interleukines ( U749 ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Gustave Roussy ( IGR ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Vectorologie et transfert de gènes ( VTG / UMR8121 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Centre National de la Recherche Scientifique ( CNRS ), University of Genova, Ghent University [Belgium] ( UGENT ), Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques ( IP-TPT ), Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) -Service de Santé des Armées-Université de Montpellier ( UM ), Université Claude Bernard Lyon 1 ( UCBL ), Apoptose, cancer et immunité ( U848 ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance Publique - Hôpitaux de Marseille (APHM)-Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli studi di Genova = University of Genoa (UniGe), Universiteit Gent = Ghent University (UGENT), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Service de Santé des Armées, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Universiteit Gent = Ghent University [Belgium] (UGENT)
Subjects: MESH: Interleukin-12, MESH : Alternative Splicing, MESH: Protein Isoforms, MESH: Lysosomal-Associated Membrane Protein 1, 0302 clinical medicine, Interferon, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Protein Isoforms, Receptor, MESH : Tumor Necrosis Factor-alpha, 0303 health sciences, MESH : Prognosis, MESH : Gastrointestinal Stromal Tumors, GiST, MESH : Lysosomal-Associated Membrane Protein 1, MESH: Alternative Splicing, MESH: Polymorphism, Single Nucleotide, MESH : Polymorphism, Single Nucleotide, General Medicine, Prognosis, Interleukin-12, MESH: Proto-Oncogene Proteins c-kit, Killer Cells, Natural, Proto-Oncogene Proteins c-kit, [SDV.IMM]Life Sciences [q-bio]/Immunology, Tumor necrosis factor alpha, MESH : Killer Cells, Natural, Sarcoma, MESH: Natural Cytotoxicity Triggering Receptor 3, Tyrosine kinase, MESH: Gastrointestinal Stromal Tumors, medicine.drug, MESH: Killer Cells, Natural, Gene isoform, MESH : Natural Cytotoxicity Triggering Receptor 3, MESH: Cell Line, Tumor, Stromal cell, MESH: Interferon-gamma, Gastrointestinal Stromal Tumors, Biology, Polymorphism, Single Nucleotide, MESH : Proto-Oncogene Proteins c-kit, MESH: Prognosis, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Interferon-gamma, Lysosomal-Associated Membrane Protein 1, Cell Line, Tumor, MESH : Interleukin-12, medicine, Humans, MESH : Interferon-gamma, 030304 developmental biology, MESH: Humans, Natural Cytotoxicity Triggering Receptor 3, MESH : Cell Line, Tumor, Tumor Necrosis Factor-alpha, MESH : Humans, MESH : Protein Isoforms, medicine.disease, Alternative Splicing, MESH: Tumor Necrosis Factor-alpha, Immunology, Cancer research, 030215 immunology
Abstract: International audience; The natural killer (NK) cell receptor NKp30 is involved in the recognition of tumor and dendritic cells (DCs). Here we describe the influence of three NKp30 splice variants on the prognosis of gastrointestinal sarcoma (GIST), a malignancy that expresses NKp30 ligands and that is treated with NK-stimulatory KIT tyrosine kinase inhibitors. Healthy individuals and those with GIST show distinct patterns of transcription of functionally different NKp30 isoforms. In a retrospective analysis of 80 individuals with GIST, predominant expression of the immunosuppressive NKp30c isoform (over the immunostimulatory NKp30a and NKp30b isoforms) was associated with reduced survival of subjects, decreased NKp30-dependent tumor necrosis factor-α (TNF-α) and CD107a release, and defective interferon-γ (IFN-γ) and interleukin-12 (IL-12) secretion in the NK-DC cross-talk that could be restored by blocking of IL-10. Preferential NKp30c expression resulted partly from a single-nucleotide polymorphism at position 3790 in the 3' untranslated region of the gene encoding NKp30. The genetically determined NKp30 status predicts the clinical outcomes of individuals with GIST independently from KIT mutation.
Published: 2010
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39. NCR3/NKp30 contributes to pathogenesis in primary Sjogren's syndrome

Author: Caroline Flament, Lindsey A. Criswell, Kathy L. Sivils, Kariman Chaba, Roland Jonsson, Gaetane Nocturne, Marie Wahren-Herlenius, Maija-Leena Eloranta, Corinne Miceli-Richard, Helena Forsblad-d'Elia, Joanne Nititham, Roald Omdal, Sylvie Rusakiewicz, Michaela Semeraro, Jacques-Eric Gottenberg, Sophie Caillat-Zucman, Lars Rönnblom, Per Eriksson, Xavier Mariette, Eric Vivier, Thierry Lazure, Nicolas Delahaye, Laurence Zitvogel, Vichnou Poirier-Colame, Gunnel Nordmark, Christopher J. Lessard, Kimberly E. Taylor, Elke Theander, Damien Sène, Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Régulation de la réponse immune, infection VIH-1 et autoimmunité, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), CEA-Direction des Energies (ex-Direction de l'Energie Nucléaire) (CEA-DES (ex-DEN)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Inserm U986, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunologie et Cancérologie Intégratives (CRC - Inserm U1138), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medical Sciences, Department of Rheumatology (Dep Rheumato - Malmo - SUEDE), Skåne University Hospital, Swedish Defence Research Agency [Stockholm] (FOI), Rosalind Russell Medical Research Center for Arthritis, Howard Hughes Medical Institute (HHMI)-University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), University of Oklahoma Health Sciences Center (OUHSC), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de rhumatologie, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Centre d'Investigation Clinique (CIC - Brest), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lymphocytes B, Autoimmunité et Immunothérapies (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), CHRU Brest - Service de Rhumatologie (CHU - BREST - Rhumato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), CEA-Direction de l'Energie Nucléaire (CEA-DEN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of California [San Francisco] (UCSF), University of California-University of California-Howard Hugues Medical Institute, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Centre d'Investigation Clinique INSERM 1412 (CIC 1412 - BREST), Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Howard Hughes Medical Institute (HHMI)-University of California [San Francisco] (UCSF), University of California-University of California, Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), 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 ), 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-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CEA-Direction de l'Energie Nucléaire ( CEA-DEN ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Institut National de la Santé et de la Recherche Médicale, 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 ), Immunologie et Cancérologie Intégratives ( CRC - Inserm U1138 ), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Department of Rheumatology ( Dep Rheumato - Malmo - SUEDE ), Swedish Defence Research Agency [Stockholm] ( FOI ), University of California [San Francisco] ( UCSF ) -Howard Hugues Medical Institute, University of Oklahoma Health Sciences Center ( OUHSC ), Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Centre d'Investigation Clinique INSERM 1412 ( CIC 1412 - BREST ), Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Lymphocyte B et Auto-immunité ( LBAI ), Université de Brest ( UBO ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHRU Brest - Service de Rhumatologie ( CHU - BREST - Rhumato ), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), and Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-LabEX IGO Immunothérapie Grand Ouest-Institut Brestois Santé Agro Matière (IBSAM)
Subjects: MESH : Cell Line, Male, MESH : Polymorphism, Genetic, [SDV]Life Sciences [q-bio], MESH : Aged, MESH : Genotype, Medical and Health Sciences, Pathogenesis, MESH: Genotype, Interferon, MESH: Reverse Transcriptase Polymerase Chain Reaction, 2.1 Biological and endogenous factors, MESH : Female, Interferon gamma, Aetiology, Cells, Cultured, MESH: Aged, Cultured, MESH: Middle Aged, Reverse Transcriptase Polymerase Chain Reaction, MESH : Reverse Transcriptase Polymerase Chain Reaction, General Medicine, MESH : Adult, Middle Aged, Biological Sciences, Sjogren's Syndrome, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Female, MESH: Natural Cytotoxicity Triggering Receptor 3, medicine.drug, MESH: Cells, Cultured, Adult, MESH : Natural Cytotoxicity Triggering Receptor 3, Genotype, MESH: Interferon-gamma, MESH : Male, Cells, Biology, Autoimmune Disease, Article, Cell Line, [ SDV.MHEP.RSOA ] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Interferon-gamma, Rare Diseases, Genetic, Clinical Research, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, MESH : Cells, Cultured, MESH: Polymorphism, Genetic, Genetics, medicine, Humans, MESH : Middle Aged, Secretion, Polymorphism, MESH : Interferon-gamma, Aged, Autoimmune disease, Polymorphism, Genetic, Natural Cytotoxicity Triggering Receptor 3, MESH: Humans, [ SDV ] Life Sciences [q-bio], Inflammatory and immune system, MESH : Humans, MESH: Adult, medicine.disease, MESH: Male, Blockade, Lymphoma, MESH: Cell Line, MESH: Sjogren's Syndrome, Cell culture, Immunology, MESH : Sjogren's Syndrome, Digestive Diseases, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease characterized by a lymphocytic exocrinopathy. However, patients often have evidence of systemic autoimmunity, and they are at markedly increased risk for the development of non- Hodgkin's lymphoma. Similar to other autoimmune disorders, a strong interferon (IFN) signature is present among subsets of pSS patients, although the precise etiology remains uncertain. NCR3/NKp30 is a natural killer (NK)-specific activating receptor regulating the cross talk between NK and dendritic cells and type II IFN secretion. We performed a case-control study of genetic polymorphisms of the NCR3/NKp30 gene and found that rs11575837 (G>A) residing in the promoter was associated with reduced gene transcription and function as well as protection to pSS. We also demonstrated that circulating levels of NCR3/NKp30 were significantly increased among pSS patients compared with controls and correlated with higher NCR3/NKp30 but not CD16-dependent IFN-γ secretion by NK cells. Excess accumulation of NK cells in minor salivary glands correlated with the severity of the exocrinopathy. B7H6, the ligand of NKp30, was expressed by salivary epithelial cells. These findings suggest that NK cells may promote an NKp30-dependent inflammatory state in salivary glands and that blockade of the B7H6/NKp30 axis could be clinically relevant in pSS.

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