Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota
Gut microbes affect immunotherapy
The unleashing of antitumor T cell responses has ushered in a new era of cancer treatment. Although these therapies can cause dramatic tumor regressions in some patients, many patients inexplicably see no benefit. Mice have been used in two studies to investigate what might be happening. Specific members of the gut microbiota influence the efficacy of this type of immunotherapy (see the Perspective by Snyder et al.). Vétizou et al. found that optimal responses to anticytotoxic T lymphocyte antigen blockade required specific Bacteroides spp. Similarly, Sivan et al. discovered that Bifidobacterium spp. enhanced the efficacy of antiprogrammed cell death ligand 1 therapy.
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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Science
Volume 350 | Issue 6264
27 November 2015
27 November 2015
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Copyright © 2015, American Association for the Advancement of Science.
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Received: 31 July 2015
Accepted: 21 October 2015
Published in print: 27 November 2015
Acknowledgments
We are grateful to the staff of the animal facility of Gustave Roussy and Institut Pasteur. The data presented in this manuscript are tabulated in the main paper and in the supplementary materials. L.Z., M.V., and P.L. have filed patent application no. EP 14190167 that relates to the following: Methods and products for modulating microbiota composition for improving the efficacy of a cancer treatment with an immune checkpoint blocker. M.V. and J.M.P. were supported by La Ligue contre le cancer and ARC, respectively. L.Z. received a special prize from the Swiss Bridge Foundation and ISREC. G.K. and L.Z. were supported by the Ligue Nationale contre le Cancer (Equipes labelisées), Agence Nationale pour la Recherche (ANR AUTOPH, ANR Emergence), European Commission (ArtForce), European Research Council Advanced Investigator Grant (to G.K.), Fondation pour la Recherche Médicale (FRM), Institut National du Cancer (INCa), Fondation de France, Cancéropôle Ile-de-France, Fondation Bettencourt-Schueller, Swiss Bridge Foundation, the LabEx Immuno-Oncology, the Institut national du cancer (SIRIC) Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM), and the Paris Alliance of Cancer Research Institutes (PACRI). S.M. was supported by NIH (R01 CA161879, as Principal Investigator). M.C. was supported by the Fondation pour la Recherche Médicale, the Fondation ARC pour la recherche sur le cancer, and Institut Nationale du Cancer. N.W. is a recipient of a Postdoctoral Fellowship from the Agence Nationale de la Recherche. A.S. was supported by BMSI YIG 2014. F.G. is supported by SIgN core funding. L.Z., M.C., and I.B.G. are all sponsored by Association pour la Recherche contre le Cancer (PGA120140200851). F.C. was supported by INCA-DGOS (GOLD H78008). N.C. was supported by INCA-DGOS (GOLD study; 2012-1-RT-14-IGR-01). L’Oreal awarded a prize to M.V. We are grateful to the staff of the animal facility of Gustave Roussy and Institut Pasteur. We thank P. Gonin, B. Ryffel, T. Angelique, N. Chanthapathet, H. Li, and S. Zuberogoitia for technical help. DNA sequence reads from this study have been submitted to the NCBI under the Bioproject IDPRJNA299112 and are available from the Sequence Read Archive (SRP Study accession SRP065109; run accession numbers SRR2758006, SRR2758031, SRR2758178, SRR2758179, SRR2758180, SRR2758181, SRR2768454, and SRR2768457.
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