Abstract IA17: Gut microbiota controls immuneresponses during cancer therapy (2016)

Abstract The tumor microenvironment is influenced by anticancer therapies, and even more so by those affecting the gut homeostasis. We reported that a deviated repertoire of the intestinal microbiome called “dysbiosis”—caused by broad spectrum antibiotics—compromised the efficacy of cyclophosphamide (CTX), an immunomodulatory alkylating agent exerting cytotoxic effects against cancer (1). Lately, we reported the importance of the gut microbiota in the efficacy of ipilimumab, a human monoclonal antibody targeting CTLA-4 (2). Mechanisms underlying this gut-cancer axis in these two therapeutic contexts are different. CTX is responsible for disrupting the gut barrier integrity as well as intestinal homeostasis, allowing a NOD2-dependent translocation of several Gram-positive bacteria into secondary lymphoid organs. CTX breaks the intestinal tolerance towards the intestinal microbiota and leads to immunization of the host against some bacterial strains. We identified a Gram positive bacteria, Enterococcus hirae, which markedly modulates the intestinal and systemic immunity through the elicitation of bacterial-specific Th1 and pathogenic Th17 cells. Moreover, we have shown that E. hirae is capable of enhancing tumor-specific CD4+ and CD8+ T cell responses against candidate tumor antigens. Finally, E. hirae specific-memory Th1 immune responses selectively predicted longer progression-free survival in advanced lung or ovarian cancer patients treated with immunotherapy and chemotherapy (platinum salts- or CTX-based chemotherapy). Altogether, E. hirae represents a valuable probiotic against cancer, an oncomicrobiotic ameliorating the efficacy of the most common alkylating immunomodulatory compound. Other oncomicrobiotics discovered in the context of CTX will be presented at this meeting (Daillère, Immunity; in press). References 1. Viaud S, Saccheri F, Mignot G, Yamazaki T, Daillère R, Hannani D, Enot DP, Pfirschke C, Engblom C, Pittet MJ, Schlitzer A, Ginhoux F, Apetoh L, Chachaty E, Woerther PL, Eberl G, Bérard M, Ecobichon C, Clermont D, Bizet C, Gaboriau-Routhiau V, Cerf-Bensussan N, Opolon P, Yessaad N, Vivier E, Ryffel B, Elson CO, Doré J, Kroemer G, Lepage P, Boneca IG, Ghiringhelli F, Zitvogel L. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 2013;342(6161):971-976. 2. Vétizou M, Pitt JM, Daillère R, Lepage P, Waldschmitt N, Flament C, Rusakiewicz S, Routy B, Roberti MP, Duong CP, 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. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 2015;350(6264):1079-84. Citation Format: Romain Daillère, Marie Vétizou, Nadine Waldschmitt, Magdalena Plebanski, Mathias Chamaillard, Vincent Cattoir, Ivo Gomperts Boneca, Laurence Zitvogel. Gut microbiota controls immuneresponses during cancer therapy [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr IA17.