Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota

Marie Vétizou(Université Paris-Sud), Jonathan M. Pitt(Université Paris-Sud), Romain Daillère(Université Paris-Sud), Patricia Lepage(Microbiologie de l’alimentation au service de la santé), Nadine Waldschmitt(Centre National de la Recherche Scientifique), Caroline Flament(Inserm), Sylvie Rusakiewicz(Inserm), Bertrand Routy(Université Paris-Sud), María P. Roberti(Inserm), Connie P.M. Duong(Inserm), Vichnou Poirier-Colame(Inserm), Antoine Roux(Délégation Paris 5), Sonia Becharef(Inserm), Silvia C. Formenti(New York University), Encouse B. Golden(New York University), Sascha Cording(Institut Pasteur), Gérard Eberl(Institut Pasteur), Andreas Schlitzer(Agency for Science, Technology and Research), Florent Ginhoux(Agency for Science, Technology and Research), Sridhar Mani(Albert Einstein College of Medicine), Takahiro Yamazaki(Inserm), Nicolas Jacquelot(Université Paris-Sud), David Enot(Délégation Paris 5), M Bérard(Institut Pasteur), Jérôme Nigou(Université Toulouse III - Paul Sabatier), Paule Opolon(Institut Gustave Roussy), Alexander Eggermont(Inserm), Paul‐Louis Woerther(Laboratoire d'études sur les monothéismes), Élisabeth Chachaty(Laboratoire d'études sur les monothéismes), Nathalie Chaput(Centre National de la Recherche Scientifique), Caroline Robert(Inserm), Christina Mateus(Institut Gustave Roussy), Guido Kroemer(Délégation Paris 5), Didier Raoult(Institut de Neurobiologie de la Méditerranée), Ivo G. Boneca(Inserm), Franck Carbonnel(Université Paris-Sud), Mathias Chamaillard(Centre National de la Recherche Scientifique), Laurence Zitvogel(Université Paris-Sud)
Science
November 5, 2015
10.1126/science.aad1329
Cited by 3,383Open Access
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Abstract

Antibodies targeting CTLA-4 have been successfully used as cancer immunotherapy. We find that the antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species. In mice and patients, T cell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA-4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade. This defect was overcome by gavage with B. fragilis, by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis-specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with antibodies against CTLA-4 favored the outgrowth of B. fragilis with anticancer properties. This study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA-4 blockade.

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