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Science. 2017 Nov 2. pii: eaan3706. doi: 10.1126/science.aan3706. [Epub ahead of print]

Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors.

Routy B1,2,3, Le Chatelier E4, Derosa L1,2,3, Duong CPM1,2,5, Alou MT1,2,3, Daillère R1,2,3, Fluckiger A1,2,5, Messaoudene M1,2, Rauber C1,2,3, Roberti MP1,2,5, Fidelle M1,3,5, Flament C1,2,5, Poirier-Colame V1,2,5, Opolon P6, Klein C7, Iribarren K8,9,10,11,12, Mondragón L8,9,10,11,12, Jacquelot N1,2,3, Qu B1,2,3, Ferrere G1,2,3, Clémenson C1,13, Mezquita L1,14, Masip JR1,14, Naltet C15, Brosseau S15, Kaderbhai C16, Richard C16, Rizvi H17, Levenez F4, Galleron N4, Quinquis B4, Pons N4, Ryffel B18, Minard-Colin V1,19, Gonin P1,20, Soria JC1,14, Deutsch E1,13, Loriot Y1,3,14, Ghiringhelli F16, Zalcman G15, Goldwasser F9,21,22, Escudier B1,14,23, Hellmann MD24,25, Eggermont A1,2,14, Raoult D26, Albiges L1,3,14, Kroemer G27,9,10,11,12,28,29, Zitvogel L30,2,3,5.

Author information

  • 1Gustave Roussy Cancer Campus (GRCC), Villejuif, France.
  • 2Institut National de la Santé et de la Recherche Medicale (INSERM) U1015 and Equipe Labellisée-Ligue Nationale contre le Cancer, Villejuif, France.
  • 3Univ. Paris-Sud, Université Paris-Saclay, Gustave Roussy, Villejuif, France.
  • 4MGP MetaGénoPolis, INRA, Université Paris-Saclay, Jouy-en-Josas, France.
  • 5Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France.
  • 6Gustave Roussy, Laboratoire de Pathologie Expérimentale, 94800 Villejuif, France.
  • 7Centre de Recherche des Cordeliers, INSERM, Université Paris Descartes, Sorbonne Paris Cité, UMRS 1138, Université Pierre et Marie Curie Université Paris 06, Sorbonne Universités, Paris, France.
  • 8Metabolomics and Cell Biology Platforms, GRCC, Villejuif, France.
  • 9Paris Descartes University, Sorbonne Paris Cité, Paris, France.
  • 10Equipe 11 Labellisée-Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.
  • 11INSERM U1138, Paris, France.
  • 12Université Pierre et Marie Curie, Paris, France.
  • 13Department of Radiation Oncology, INSERM U1030, and Molecular Radiotherapy, Gustave Roussy, Université Paris-Saclay, F-94805 Villejuif, France.
  • 14Department of Medical Oncology, Gustave Roussy, Villejuif, France.
  • 15Thoracic Oncology Department-CIC1425/CLIP2 Paris-Nord, Hospital Bichat-Claude Bernard, AP-HP, Université Paris-Diderot, Paris, France.
  • 16Department of medical oncology, Center GF Leclerc, Dijon, France.
  • 17Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 18Molecular Immunology and Embryology, UMR 7355, CNRS, University of Orleans, Orléans, France.
  • 19Department of Pediatric Oncology, GRCC, Villejuif, France.
  • 20Preclinical Research Platform, GRCC, Villejuif, France.
  • 21Department of Medical Oncology, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
  • 22Immunomodulatory Therapies Multidisciplinary Study Group (CERTIM), Paris, France.
  • 23INSERM U981, GRCC, Villejuif, France.
  • 24Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 25Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
  • 26URMITE, Aix Marseille Université, UM63, CNRS 7278, IRD 198, INSERM 1095, IHU-Méditerranée Infection, 13005 Marseille, France.
  • 27Metabolomics and Cell Biology Platforms, GRCC, Villejuif, France. laurence.zitvogel@gustaveroussy.fr kroemer@orange.fr.
  • 28Pôle de Biologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France.
  • 29Department of Women's and Children's Health, Karolinska University Hospital, 17176 Stockholm, Sweden.
  • 30Gustave Roussy Cancer Campus (GRCC), Villejuif, France. laurence.zitvogel@gustaveroussy.fr kroemer@orange.fr.

Abstract

Immune checkpoint inhibitors (ICI) targeting the PD-1/PD-L1 axis induce sustained clinical responses in a sizeable minority of cancer patients. Here, we show that primary resistance to ICI can be due to abnormal gut microbiome composition. Antibiotics (ATB) inhibited the clinical benefit of ICI in patients with advanced cancer. Fecal microbiota transplantation (FMT) from cancer patients who responded to ICI (but not from non-responding patients) into germ-free or ATB-treated mice ameliorated the antitumor effects of PD-1 blockade. Metagenomics of patient stools at diagnosis revealed correlations between clinical responses to ICI and the relative abundance of Akkermansia muciniphila Oral supplementation with A. muciniphila post-FMT with non-responder feces restored the efficacy of PD-1 blockade in an IL-12-dependent manner, by increasing the recruitment of CCR9+CXCR3+CD4+ T lymphocytes into tumor beds.

PMID:
29097494
DOI:
10.1126/science.aan3706
[PubMed - as supplied by publisher]
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