Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota PMID: 26541610

RQC and Longevity Regulation

2026-09-03

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

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

Marie Vétizou ¹ , Jonathan M Pitt ¹ , Romain Daillère ¹ , Patricia Lepage ² , Nadine Waldschmitt ³ , Caroline Flament ⁴ , Sylvie Rusakiewicz ⁴ , Bertrand Routy ⁵ , Maria P Roberti ⁴ , Connie P M Duong ⁴ , Vichnou Poirier-Colame ⁴ , Antoine Roux ⁶ , Sonia Becharef ⁴ , Silvia Formenti ⁷ , Encouse Golden ⁷ , Sascha Cording ⁸ , Gerard Eberl ⁸ , Andreas Schlitzer ⁹ , Florent Ginhoux ⁹ , Sridhar Mani ¹⁰ , Takahiro Yamazaki ⁴ , Nicolas Jacquelot ¹ , David P Enot ¹¹ , Marion Bérard ¹² , Jérôme Nigou ¹³ , Paule Opolon ¹⁴ , Alexander Eggermont ¹⁵ , Paul-Louis Woerther ¹⁶ , Elisabeth Chachaty ¹⁶ , Nathalie Chaput ¹⁷ , Caroline Robert ¹⁸ , Christina Mateus ¹⁹ , Guido Kroemer ²⁰ , Didier Raoult ²¹ , Ivo Gomperts Boneca ²² , Franck Carbonnel ²³ , Mathias Chamaillard ³ , Laurence Zitvogel ²⁴

Affiliations

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. [email protected].

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.