title: Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota.
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.
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. INSERM U1015, GRCC, Villejuif, France. University of Paris Sud XI, Kremlin-Bicêtre, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Vétizou
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. INSERM U1015, GRCC, Villejuif, France. University of Paris Sud XI, Kremlin-Bicêtre, France.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Pitt
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. INSERM U1015, GRCC, Villejuif, France. University of Paris Sud XI, Kremlin-Bicêtre, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Daillère
authors.affiliation: Institut National de la Recherche Agronomique (INRA), Micalis-UMR1319, 78360 Jouy-en-Josas, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Lepage
authors.affiliation: University of Lille, CNRS, INSERM, Centre Hospitalier Régional Universitaire de Lille, Institut Pasteur de Lille, U1019, UMR 8204, Centre d'Infection et d'Immunité de Lille (CIIL), F-59000 Lille, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Waldschmitt
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. INSERM U1015, GRCC, Villejuif, France. Center of Clinical Investigations in Biotherapies of Cancer 1428, Villejuif, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Flament
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. INSERM U1015, GRCC, Villejuif, France. Center of Clinical Investigations in Biotherapies of Cancer 1428, Villejuif, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Rusakiewicz
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. INSERM U1015, GRCC, Villejuif, France. University of Paris Sud XI, Kremlin-Bicêtre, France. Center of Clinical Investigations in Biotherapies of Cancer 1428, Villejuif, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Routy
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. INSERM U1015, GRCC, Villejuif, France. Center of Clinical Investigations in Biotherapies of Cancer 1428, Villejuif, France.
authors.forename: Maria P
authors.initials: MP
authors.lastname: Roberti
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. INSERM U1015, GRCC, Villejuif, France. Center of Clinical Investigations in Biotherapies of Cancer 1428, Villejuif, France.
authors.forename: Connie P M
authors.initials: CP
authors.lastname: Duong
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. INSERM U1015, GRCC, Villejuif, France. Center of Clinical Investigations in Biotherapies of Cancer 1428, Villejuif, France.
authors.forename: Vichnou
authors.initials: V
authors.lastname: Poirier-Colame
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. INSERM U1015, GRCC, Villejuif, France. Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Roux
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. INSERM U1015, GRCC, Villejuif, France. Center of Clinical Investigations in Biotherapies of Cancer 1428, Villejuif, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Becharef
authors.affiliation: Department of Radiation Oncology, New York University, New York, NY, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Formenti
authors.affiliation: Department of Radiation Oncology, New York University, New York, NY, USA.
authors.forename: Encouse
authors.initials: E
authors.lastname: Golden
authors.affiliation: Microenvironment and Immunity Unit, Institut Pasteur, Paris, France.
authors.forename: Sascha
authors.initials: S
authors.lastname: Cording
authors.affiliation: Microenvironment and Immunity Unit, Institut Pasteur, Paris, France.
authors.forename: Gerard
authors.initials: G
authors.lastname: Eberl
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schlitzer
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
authors.forename: Florent
authors.initials: F
authors.lastname: Ginhoux
authors.affiliation: Department of Genetics and Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Mani
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. INSERM U1015, GRCC, Villejuif, France. Center of Clinical Investigations in Biotherapies of Cancer 1428, Villejuif, France.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamazaki
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. INSERM U1015, GRCC, Villejuif, France. University of Paris Sud XI, Kremlin-Bicêtre, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Jacquelot
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. Université Paris Descartes, Sorbonne Paris Cité, Paris, France. Metabolomics Platform, GRCC, Villejuif, France.
authors.forename: David P
authors.initials: DP
authors.lastname: Enot
authors.affiliation: Animalerie Centrale, Institut Pasteur, Paris, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Bérard
authors.affiliation: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale (IPBS), Toulouse, France. Université de Toulouse, Université Paul Sabatier, IPBS, F-31077 Toulouse, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Nigou
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Paule
authors.initials: P
authors.lastname: Opolon
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. INSERM U1015, GRCC, Villejuif, France. Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France.
authors.forename: Alexander
authors.initials: A
authors.lastname: Eggermont
authors.affiliation: Service de microbiologie, GRCC, Villejuif, France.
authors.forename: Paul-Louis
authors.initials: PL
authors.lastname: Woerther
authors.affiliation: Service de microbiologie, GRCC, Villejuif, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Chachaty
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. Laboratory of Immunomonitoring in Oncology, UMS 3655 CNRS/US 23 INSERM, GRCC, Villejuif, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chaput
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France. INSERM U981, GRCC, Villejuif, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Robert
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France.
authors.forename: Christina
authors.initials: C
authors.lastname: Mateus
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, Paris, France. Metabolomics Platform, GRCC, Villejuif, France. INSERM U848, Villejuif, France. Equipe 11 Labellisée-Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, Paris, France. Pôle de Biologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.affiliation: Unité des Rickettsies, Faculté de Médecine, Université de la Méditerranée, Marseille, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Raoult
authors.affiliation: Institut Pasteur, Unit of Biology and Genetics of the Bacterial Cell Wall, Paris, France. INSERM, Equipe Avenir, Paris, France.
authors.forename: Ivo Gomperts
authors.initials: IG
authors.lastname: Boneca
authors.affiliation: University of Paris Sud XI, Kremlin-Bicêtre, France. Gastroenterology Department, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Carbonnel
authors.affiliation: University of Lille, CNRS, INSERM, Centre Hospitalier Régional Universitaire de Lille, Institut Pasteur de Lille, U1019, UMR 8204, Centre d'Infection et d'Immunité de Lille (CIIL), F-59000 Lille, France.
authors.forename: Mathias
authors.initials: M
authors.lastname: Chamaillard
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. INSERM U1015, GRCC, Villejuif, France. University of Paris Sud XI, Kremlin-Bicêtre, France. Center of Clinical Investigations in Biotherapies of Cancer 1428, Villejuif, France. laurence.zitvogel@gustaveroussy.fr.
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D001439:Bacteroides / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology; D064806:Dysbiosis / Q000276:immunology; D000069467:Fecal Microbiota Transplantation; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000187:drug effects / Q000276:immunology*; D005856:Germ-Free Life / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D007167:Immunotherapy; D007422:Intestines / Q000276:immunology / Q000382:microbiology; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D012878:Skin Neoplasms / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen; D000074324:Ipilimumab