Gut microbiota enhance the cytotoxic activity of anticancer immuno- and chemotherapies.

  • Major finding: Gut microbiota enhance the cytotoxic activity of anticancer immuno- and chemotherapies.

  • Mechanism: Commensal bacteria promote generation of proinflammatory cytokines, ROS, and pTH17 cells.

  • Impact: Manipulation of human gut microbes may improve therapeutic responses to anticancer agents.

Gut commensal microbiota modulate both local and systemic inflammatory responses, and disruption of the microbial balance, or dysbiosis, has been implicated in chronic inflammation–associated colon cancer. However, whether intestinal bacteria regulate anticancer therapy responses remains unknown. Iida and colleagues found that dysregulation of commensal microbiota via antibiotic treatment or use of germ-free mice impaired inhibition of tumor growth by CpG-oligodeoxynucleotide immunotherapy, suggesting that intestinal bacteria modify anticancer immune responses in the tumor microenvironment. Indeed, commensal microbiota and expression of Toll-like receptor 4 were required for induction of proinflammatory cytokines, including TNF, by tumor-associated myeloid cells. In addition, microbiota were also necessary for the early cytotoxic response to platinum chemotherapeutic compounds; elimination of microbiota reduced myeloid-cell generation of reactive oxygen species (ROS) in response to oxaliplatin, resulting in decreased DNA damage and diminished tumor cell death. In another study, Viaud and colleagues found that cyclophosphamide, which induces antitumor immune responses, stimulated translocation of specific Gram-positive commensal bacteria into lymph nodes and the spleen and dysbiosis in the small intestine of tumor-bearing mice. This subset of bacteria was necessary and sufficient for cyclophosphamide-induced polarization of pathogenic T-helper (TH) 17 (pTH17) cells and bacteria-specific TH1 memory cells in the spleen. Furthermore, pTH17-cell and TH1-cell accumulation and cyclophosphamide-mediated inhibition of tumor growth were suppressed in the absence of commensal bacteria in multiple mouse tumor models, whereas adoptive transfer of pTH17 cells restored the anticancer efficacy of cyclophosphamide in antibiotic-treated mice, supporting a critical role for pTH17 cells in inducing the cytotoxic effects of chemotherapy. Together, these findings indicate that commensal bacteria mediate efficient therapeutic responses to various anticancer agents via modulation of antitumor immune responses and suggest that manipulation of intestinal bacteria may enhance the efficacy of these treatments.

Iida N, Dzutsev A, Stewart CA, Smith L, Bouladoux N, Weingarten RA, et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 2013;342:967–70.

Viaud S, Saccheri F, Mignot G, Yamazaki T, Daillère R, Hannani D, et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 2013;342:971–6.

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