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. 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

Bertrand Routy  1   2   3 , Emmanuelle Le Chatelier  4 , Lisa Derosa  1   2   3 , Connie P M Duong  1   2   5 , Maryam Tidjani Alou  1   2   3 , Romain Daillère  1   2   3 , Aurélie Fluckiger  1   2   5 , Meriem Messaoudene  1   2 , Conrad Rauber  1   2   3 , Maria P Roberti  1   2   5 , Marine Fidelle  1   3   5 , Caroline Flament  1   2   5 , Vichnou Poirier-Colame  1   2   5 , Paule Opolon  6 , Christophe Klein  7 , Kristina Iribarren  8   9   10   11   12 , Laura Mondragón  8   9   10   11   12 , Nicolas Jacquelot  1   2   3 , Bo Qu  1   2   3 , Gladys Ferrere  1   2   3 , Céline Clémenson  1   13 , Laura Mezquita  1   14 , Jordi Remon Masip  1   14 , Charles Naltet  15 , Solenn Brosseau  15 , Coureche Kaderbhai  16 , Corentin Richard  16 , Hira Rizvi  17 , Florence Levenez  4 , Nathalie Galleron  4 , Benoit Quinquis  4 , Nicolas Pons  4 , Bernhard Ryffel  18 , Véronique Minard-Colin  1   19 , Patrick Gonin  1   20 , Jean-Charles Soria  1   14 , Eric Deutsch  1   13 , Yohann Loriot  1   3   14 , François Ghiringhelli  16 , Gérard Zalcman  15 , François Goldwasser  9   21   22 , Bernard Escudier  1   14   23 , Matthew D Hellmann  24   25 , Alexander Eggermont  1   2   14 , Didier Raoult  26 , Laurence Albiges  1   3   14 , Guido Kroemer  27   9   10   11   12   28   29 , Laurence Zitvogel  30   2   3   5
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Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors

Bertrand Routy et al. Science. .

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.

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