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Science. 2015 Nov 27;350(6264):1079-84. doi: 10.1126/science.aad1329. Epub 2015 Nov 5.

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

Author information

1
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.
2
Institut National de la Recherche Agronomique (INRA), Micalis-UMR1319, 78360 Jouy-en-Josas, France.
3
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.
4
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.
5
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.
6
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.
7
Department of Radiation Oncology, New York University, New York, NY, USA.
8
Microenvironment and Immunity Unit, Institut Pasteur, Paris, France.
9
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
10
Department of Genetics and Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
11
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.
12
Animalerie Centrale, Institut Pasteur, Paris, France.
13
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.
14
Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France.
15
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.
16
Service de microbiologie, GRCC, Villejuif, France.
17
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.
18
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.
19
Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France. Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France.
20
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.
21
Unité des Rickettsies, Faculté de Médecine, Université de la Méditerranée, Marseille, France.
22
Institut Pasteur, Unit of Biology and Genetics of the Bacterial Cell Wall, Paris, France. INSERM, Equipe Avenir, Paris, France.
23
University of Paris Sud XI, Kremlin-Bicêtre, France. Gastroenterology Department, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Paris, France.
24
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.

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.

PMID:
26541610
PMCID:
PMC4721659
DOI:
10.1126/science.aad1329
[Indexed for MEDLINE]
Free PMC Article

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