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

Marie Vétizou, Jonathan M. Pitt, Romain Daillère, Patricia Lepage, Nadine Waldschmitt, Caroline Flament, Sylvie Rusakiewicz, Bertrand Routy, Maria P. Roberti, Connie P M Duong, Vichnou Poirier-Colame, Antoine Roux, Sonia Becharef, Silvia Formenti, Encouse Golden, Sascha Cording, Gerard Eberl, Andreas Schlitzer, Florent Ginhoux, Sridhar ManiTakahiro Yamazaki, Nicolas Jacquelot, David P. Enot, Marion Bérard, Jérôme Nigou, Paule Opolon, Alexander Eggermont, Paul Louis Woerther, Elisabeth Chachaty, Nathalie Chaput, Caroline Robert, Christina Mateus, Guido Kroemer, Didier Raoult, Ivo Gomperts Boneca, Franck Carbonnel, Mathias Chamaillard, Laurence Zitvogel

Research output: Contribution to journalArticle

738 Citations (Scopus)

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,Tcell 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.

Original languageEnglish (US)
Pages (from-to)1079-1084
Number of pages6
JournalScience
Volume350
Issue number6264
DOIs
StatePublished - Nov 27 2015

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Immunotherapy
Bacteroides
Adoptive Transfer
Antibodies
Polysaccharides
Melanoma
Immunization
Neoplasms
Anti-Bacterial Agents
T-Lymphocytes
Gastrointestinal Microbiome
Therapeutics
Fecal Microbiota Transplantation

ASJC Scopus subject areas

  • General
  • Medicine(all)

Cite this

Vétizou, M., Pitt, J. M., Daillère, R., Lepage, P., Waldschmitt, N., Flament, C., ... Zitvogel, L. (2015). Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science, 350(6264), 1079-1084. https://doi.org/10.1126/science.aad1329

Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. / Vétizou, Marie; Pitt, Jonathan M.; Daillère, Romain; Lepage, Patricia; Waldschmitt, Nadine; Flament, Caroline; Rusakiewicz, Sylvie; Routy, Bertrand; Roberti, Maria P.; Duong, Connie P M; Poirier-Colame, Vichnou; Roux, Antoine; Becharef, Sonia; Formenti, Silvia; Golden, Encouse; Cording, Sascha; Eberl, Gerard; Schlitzer, Andreas; Ginhoux, Florent; Mani, Sridhar; Yamazaki, Takahiro; Jacquelot, Nicolas; Enot, David P.; Bérard, Marion; Nigou, Jérôme; Opolon, Paule; Eggermont, Alexander; Woerther, Paul Louis; Chachaty, Elisabeth; Chaput, Nathalie; Robert, Caroline; Mateus, Christina; Kroemer, Guido; Raoult, Didier; Boneca, Ivo Gomperts; Carbonnel, Franck; Chamaillard, Mathias; Zitvogel, Laurence.

In: Science, Vol. 350, No. 6264, 27.11.2015, p. 1079-1084.

Research output: Contribution to journalArticle

Vétizou, M, Pitt, JM, Daillère, R, Lepage, P, Waldschmitt, N, Flament, C, Rusakiewicz, S, Routy, B, Roberti, MP, Duong, CPM, Poirier-Colame, V, Roux, A, Becharef, S, Formenti, S, Golden, E, Cording, S, Eberl, G, Schlitzer, A, Ginhoux, F, Mani, S, Yamazaki, T, Jacquelot, N, Enot, DP, Bérard, M, Nigou, J, Opolon, P, Eggermont, A, Woerther, PL, Chachaty, E, Chaput, N, Robert, C, Mateus, C, Kroemer, G, Raoult, D, Boneca, IG, Carbonnel, F, Chamaillard, M & Zitvogel, L 2015, 'Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota', Science, vol. 350, no. 6264, pp. 1079-1084. https://doi.org/10.1126/science.aad1329
Vétizou M, Pitt JM, Daillère R, Lepage P, Waldschmitt N, Flament C et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015 Nov 27;350(6264):1079-1084. https://doi.org/10.1126/science.aad1329
Vétizou, Marie ; Pitt, Jonathan M. ; Daillère, Romain ; Lepage, Patricia ; Waldschmitt, Nadine ; Flament, Caroline ; Rusakiewicz, Sylvie ; Routy, Bertrand ; Roberti, Maria P. ; Duong, Connie P M ; Poirier-Colame, Vichnou ; Roux, Antoine ; Becharef, Sonia ; Formenti, Silvia ; Golden, Encouse ; Cording, Sascha ; Eberl, Gerard ; Schlitzer, Andreas ; Ginhoux, Florent ; Mani, Sridhar ; Yamazaki, Takahiro ; Jacquelot, Nicolas ; Enot, David P. ; Bérard, Marion ; Nigou, Jérôme ; Opolon, Paule ; Eggermont, Alexander ; Woerther, Paul Louis ; Chachaty, Elisabeth ; Chaput, Nathalie ; Robert, Caroline ; Mateus, Christina ; Kroemer, Guido ; Raoult, Didier ; Boneca, Ivo Gomperts ; Carbonnel, Franck ; Chamaillard, Mathias ; Zitvogel, Laurence. / Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. In: Science. 2015 ; Vol. 350, No. 6264. pp. 1079-1084.
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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,Tcell 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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