Journal Article

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

Pons, Nicolas, Fluckiger, Aurélie, Zitvogel, Laurence, Fidelle, Marine, Rizvi, Hira, Roberti, Maria P., Rauber, Conrad, Hellmann, Matthew D., Opolon, Paule, Le Chatelier, Emmanuelle, Clémenson, Céline, Mezquita, Laura, Messaoudene, Meriem, Klein, Christophe, Qu, Bo, Kaderbhai, Coureche, Flament, Caroline, Levenez, Florence, Zalcman, Gérard, Kroemer, Guido, Ghiringhelli, François, Derosa, Lisa, Eggermont, Alexander, Quinquis, Benoit, Soria, Jean-Charles, Duong, Connie P. M., Brosseau, Solenn, Ryffel, Bernhard, Routy, Bertrand, Ferrere, Gladys, Poirier-Colame, Vichnou, Mondragón, Laura, Loriot, Yohann, Minard-Colin, Véronique, Masip, Jordi Remon, Richard, Corentin, Escudier, Bernard, Deutsch, Eric, Jacquelot, Nicolas, Daillère, Romain, Galleron, Nathalie, Iribarren, Kristina, Goldwasser, François, Raoult, Didier, Gonin, Patrick, Alou, Maryam Tidjani, Naltet, Charles, Albiges, Laurence

2018

Overview

Resident gut bacteria can affect patient responses to cancer immunotherapy (see the Perspective by Jobin). Routy et al. show that antibiotic consumption is associated with poor response to immunotherapeutic PD-1 blockade. They profiled samples from patients with lung and kidney cancers and found that nonresponding patients had low levels of the bacterium Akkermansia muciniphila . Oral supplementation of the bacteria to antibiotic-treated mice restored the response to immunotherapy. Matson et al. and Gopalakrishnan et al. studied melanoma patients receiving PD-1 blockade and found a greater abundance of “good” bacteria in the guts of responding patients. Nonresponders had an imbalance in gut flora composition, which correlated with impaired immune cell activity. Thus, maintaining healthy gut flora could help patients combat cancer. Science , this issue p. 91 , p. 104 , p. 97 ; see also p. 32 Gut bacteria influence patient response to cancer therapy. 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.

• Publisher: The American Association for the Advancement of Science,American Association for the Advancement of Science (AAAS)
• Subject: Abundance / Akkermansia muciniphila / Animals / Anti-Bacterial Agents - therapeutic use / Antibiotics / Antibodies, Monoclonal - therapeutic use / Anticancer properties / Antitumor activity / Bacteria / Cancer / Cancer immunotherapy / CCR9 protein / CD4 antigen / CD4 Antigens - immunology / CXCR3 protein / Dietary supplements / Digestive system / Fecal Microbiota Transplantation / Fecal microflora / Feces / Feces - microbiology / Feedback (Response) / Gastrointestinal Microbiome - genetics / Gastrointestinal Microbiome - immunology / Germfree / Humans / Immune checkpoint inhibitors / Immunology / Immunotherapy / Immunotherapy - methods / Interleukin 12 / Interleukin-12 - immunology / Intestinal microflora / Kidney cancer / Kidneys / Life Sciences / Lungs / Lymphocytes / Lymphocytes T / Melanoma / Metagenome - genetics / Mice / Microbiomes / Microbiota / Neoplasms - therapy / Patients / PD-1 protein / PD-L1 protein / Programmed Cell Death 1 Receptor - antagonists & inhibitors / Receptors, CCR - immunology / Receptors, CXCR3 - immunology / Relative abundance / T-Lymphocytes - immunology / Transplantation / Tumors / Verrucomicrobia - genetics / Verrucomicrobia - immunology