Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer
| العنوان: | Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer |
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| المؤلفون: | Julien Schmidt, Ludovic Lacroix, Atmane Seck, Aurore Vozy, Patrick Saulnier, Jonathan Grivel, Nathalie Chaput, Jean Mehdi Jouniaux, Ester Simeone, Franck Carbonnel, Paolo A. Ascierto, Laetitia Nebot-Bral, M. Naigeon, Domenico Mallardo, L. Boselli, Paul Louis Woerther, Caroline Robert, Lydie Cassard, Patricia Lepage, Angelo Paci, Clélia Coutzac, Mélanie Desbois, Christine Mateus, V. Asvatourian, Emilie Soularue |
| المساهمون: | Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France, Laboratoire d’Immunomonitoring en Oncologie (LIO), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), 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), Faculté de Médecine Paris-Saclay, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris-Saclay, Institut Gustave Roussy (IGR), Vectorologie et thérapeutiques anti-cancéreuses [Villejuif] (UMR 8203), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay, Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan], Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, IRCCS Istituto Nazionale dei Tumori [Milano], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Instituto Nazionale Tumori-Fondazione 'G. Pascale', Direction de la recherche [Gustave Roussy], Fondation Gustave Roussy Direction Générale de l’offre de Soins, DGOS: TRANSLA 12-174 Institut National de la Santé et de la Recherche Médicale, Inserm Centre National de la Recherche Scientifique, CNRS: INCa-DGOS-INSERM_12551, ANR-10IBHU-0001 Fondation Gustave Roussy Institut National Du Cancer, INCa: 2012-1-RT-14-IGR-01 Fondation pour la Recherche Médicale, FRM AstraZeneca Sanofi GlaxoSmithKline Australia, GSK, The authors thank Dr. Patrick Gonin from the PlatForm for Preclinical Evaluation (PFEP). Fundings: This study was funded by Gustave Roussy Cancer Campus, Fondation Gustave Roussy, the Institut national de la santé et de la recherche médicale (INSERM), the Centre national de la recherche scientifique (CNRS), SIRIC SOCRATE (INCa DGOS INSERM 6043), SIRIC SOCRATE 2.0 (INCa-DGOS-INSERM_12551), MMO program: ANR-10IBHU-0001), Direction General de l’Offre de Soins (DGOS, TRANSLA 12-174), Institut National du Cancer (INCa, 2012-062 N_ Canceropole: 2012-1-RT-14-IGR-01). Dr. Clélia Coutzac was supported by fellowships from Fondation pour la Recherche Medicale (FRM) from 2015 to 2016., N.C. reports research grants from Cytune Pharma, GSK, Sanofi, has participated in advisory boards for AstraZeneca and has been a speaker for Sanofi and AstraZeneca. C.R. has participated in advisory boards for Roche, GSK, Merck, Novartis, Amgen, BMS and Novartis. Franck Carbonnel received boards or lecture fees from enterome, Amgen, Astra, MSD, BMS, Janssen, Pfizer, Abbvie, Mayoly Spindler, Takeda, Pileje, Roche. E. Soularue has participated in advisory board for Novartis. L.L. has participated in advisory boards for Roche, Astrazeneca, BMS, Genomic Health, Illumina, Qiagen, Novartis Thermofisher and has been a speaker for Amgen, AstraZeneca, Dyn, Vela diagnostics, Luye Pharma, and Roche. P.A.A. has/had a consultant/advisory role for Bristol Myers-Squibb, Roche-Genentech, Merck Sharp & Dohme, Array, Novartis, Amgen, Merck Serono, Pierre Fabre, Incyte, NewLink Genetics, Genmab, Medimmune, AstraZeneca, Syndax, SunPharma, Sanofi, Idera. He also received Research funds from Bristol Myers-Squibb, Roche-Genentech, Array. The other authors have no conflicts of interest to declare., ANR-10-IBHU-0001,MMO (IHU-CANCER),Institut de Médecine Personnalisée du Cancer(2010) |
| المصدر: | Nature Communications Nature Communications, Nature Publishing Group, 2020, 11 (1), ⟨10.1038/s41467-020-16079-x⟩ Nature Communications, Vol 11, Iss 1, Pp 1-13 (2020) |
| بيانات النشر: | Springer Science and Business Media LLC, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, [SDV]Life Sciences [q-bio], T-Lymphocytes, medicine.medical_treatment, General Physics and Astronomy, Pharmacology, Gut flora, T-Lymphocytes, Regulatory, Immune tolerance, Tumour biomarkers, Mice, 0302 clinical medicine, Neoplasms, RNA, Ribosomal, 16S, CTLA-4 Antigen, lcsh:Science, Cancer, Mice, Inbred BALB C, Multidisciplinary, biology, Chemistry, hemic and immune systems, 3. Good health, Butyrates, 030220 oncology & carcinogenesis, B7-1 Antigen, Science, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, chemical and pharmacologic phenomena, Butyrate, digestive system, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Immune system, Biomarkers, Tumor, medicine, Animals, Humans, CD86, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Dendritic Cells, General Chemistry, Immunotherapy, Fatty Acids, Volatile, biology.organism_classification, Ipilimumab, Gastrointestinal Microbiome, 030104 developmental biology, CTLA-4, lcsh:Q, B7-2 Antigen, Propionates, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Biomarkers, CD80 |
| الوصف: | Gut microbiota composition influences the clinical benefit of immune checkpoints in patients with advanced cancer but mechanisms underlying this relationship remain unclear. Molecular mechanism whereby gut microbiota influences immune responses is mainly assigned to gut microbial metabolites. Short-chain fatty acids (SCFA) are produced in large amounts in the colon through bacterial fermentation of dietary fiber. We evaluate in mice and in patients treated with anti-CTLA-4 blocking mAbs whether SCFA levels is related to clinical outcome. High blood butyrate and propionate levels are associated with resistance to CTLA-4 blockade and higher proportion of Treg cells. In mice, butyrate restrains anti-CTLA-4-induced up-regulation of CD80/CD86 on dendritic cells and ICOS on T cells, accumulation of tumor-specific T cells and memory T cells. In patients, high blood butyrate levels moderate ipilimumab-induced accumulation of memory and ICOS + CD4 + T cells and IL-2 impregnation. Altogether, these results suggest that SCFA limits anti-CTLA-4 activity. The gut microbiota has been reported to regulate the efficacy of cancer therapy. Here, the authors show that short-chain fatty acids, which are generated through bacterial fermentation, increases immune tolerance leading to resistance to anti-CTLA-4 immunotherapy in mice and patients with metastatic melanoma. |
| تدمد: | 2041-1723 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c3cce94443436fc757640bcdfcf82411 https://doi.org/10.1038/s41467-020-16079-x |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....c3cce94443436fc757640bcdfcf82411 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20411723 |
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