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Science. 2018 Jan 5;359(6371):91-97. doi: 10.1126/science.aan3706. Epub 2017 Nov 2.

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

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

Abstract

Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis induce sustained clinical responses in a sizable minority of cancer patients. We found that primary resistance to ICIs can be attributed to abnormal gut microbiome composition. Antibiotics inhibited the clinical benefit of ICIs in patients with advanced cancer. Fecal microbiota transplantation (FMT) from cancer patients who responded to ICIs into germ-free or antibiotic-treated mice ameliorated the antitumor effects of PD-1 blockade, whereas FMT from nonresponding patients failed to do so. Metagenomics of patient stool samples at diagnosis revealed correlations between clinical responses to ICIs and the relative abundance of Akkermansia muciniphila Oral supplementation with A. muciniphila after FMT with nonresponder feces restored the efficacy of PD-1 blockade in an interleukin-12-dependent manner by increasing the recruitment of CCR9+CXCR3+CD4+ T lymphocytes into mouse tumor beds.

PMID:
29097494
DOI:
10.1126/science.aan3706
[Indexed for MEDLINE]

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