Résumé
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 FMTwith 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.
langue originale | Anglais |
---|---|
Pages (de - à) | 91-97 |
Nombre de pages | 7 |
journal | Science |
Volume | 359 |
Numéro de publication | 6371 |
Les DOIs | |
état | Publié - 5 janv. 2018 |
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Dans: Science, Vol 359, Numéro 6371, 05.01.2018, p. 91-97.
Résultats de recherche: Contribution à un journal › Article › Revue par des pairs
TY - JOUR
T1 - Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors
AU - Routy, Bertrand
AU - Le Chatelier, Emmanuelle
AU - Derosa, Lisa
AU - Duong, Connie P.M.
AU - Alou, Maryam Tidjani
AU - Daillère, Romain
AU - Fluckiger, Aurélie
AU - Messaoudene, Meriem
AU - Rauber, Conrad
AU - Roberti, Maria P.
AU - Fidelle, Marine
AU - Flament, Caroline
AU - Poirier-Colame, Vichnou
AU - Opolon, Paule
AU - Klein, Christophe
AU - Iribarren, Kristina
AU - Mondragón, Laura
AU - Jacquelot, Nicolas
AU - Qu, Bo
AU - Ferrere, Gladys
AU - Clémenson, Céline
AU - Mezquita, Laura
AU - Masip, Jordi Remon
AU - Naltet, Charles
AU - Brosseau, Solenn
AU - Kaderbhai, Coureche
AU - Richard, Corentin
AU - Rizvi, Hira
AU - Levenez, Florence
AU - Galleron, Nathalie
AU - Quinquis, Benoit
AU - Pons, Nicolas
AU - Ryffel, Bernhard
AU - Minard-Colin, Véronique
AU - Gonin, Patrick
AU - Soria, Jean Charles
AU - Deutsch, Eric
AU - Loriot, Yohann
AU - Ghiringhelli, François
AU - Zalcman, Gérard
AU - Goldwasser, François
AU - Escudier, Bernard
AU - Hellmann, Matthew D.
AU - Eggermont, Alexander
AU - Raoult, Didier
AU - Albiges, Laurence
AU - Kroemer, Guido
AU - Zitvogel, Laurence
N1 - Funding Information: Archive (EMBL-EBI) under accession number PRJEB22863. B.R. was supported by Gustave Roussy Course of Excellence in Oncology–Fondation Philanthropia and a McGill University Townsend hematology research fellowship award. L.Z. and G.K. were supported by the Ligue contre le Cancer (équipe labelisée), Agence Nationale de la Recherche (ANR)–Projets blancs, ANR under the frame of E-Rare-2 (ERA-Net for Research on Rare Diseases), Association pour la recherche sur le cancer (ARC), Cancéropôle Ile-de-France, Institut National du Cancer (INCa), Institut Universitaire de France, Fondation pour la Recherche Médicale (FRM), the European Commission (ArtForce), the European Research Council (ERC), the LeDucq Foundation, LabEx Immuno-Oncology, SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE), SIRIC Cancer Research and Personalized Medicine (CARPEM), the Paris Alliance of Cancer Research Institutes (PACRI), and philanthropia (E. Badinter and N. Meyer). L.Z., E.L.C., and B.R. are inventors on patent EP17305206 and European license 16306779.6 held by Institut Gustave Roussy that covers use of microbial modulators for PD1/PD-L1/PD-L2 mAb-based treatments. L.Z. and G.K. are cofounders of EverImmune, a biotech company focused on the use of commensal bacteria for cancer treatment.
PY - 2018/1/5
Y1 - 2018/1/5
N2 - 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 FMTwith 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.
AB - 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 FMTwith 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.
UR - http://www.scopus.com/inward/record.url?scp=85033576428&partnerID=8YFLogxK
U2 - 10.1126/science.aan3706
DO - 10.1126/science.aan3706
M3 - Article
C2 - 29097494
AN - SCOPUS:85033576428
SN - 0036-8075
VL - 359
SP - 91
EP - 97
JO - Science
JF - Science
IS - 6371
ER -