Editors' ChoiceCancer

Not just a fecal matter

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Science Translational Medicine  02 Dec 2015:
Vol. 7, Issue 316, pp. 316ec207
DOI: 10.1126/scitranslmed.aad8023

Gut microbiota influences both local and systemic inflammation and modulates the efficacy of traditional cytotoxic chemotherapies and immunotherapy in murine models. Although intact commensal gut microbiota are thought to be required for optimal responses to cancer therapeutics, the specific effect of commensal flora on the therapeutic efficacy of immune checkpoint blocking agents and their immune-related intestinal toxicity remains uncertain.

In a new study, Vétizou et al. found that gut microbiota was required for the anticancer effects of antibodies targeting cytotoxic T lymphocyte antigen-4 (CTLA-4) in sarcoma, melanoma, and colon cancer mouse models. Anti–CTLA-4 controlled tumor progression in specific pathogen-free but not in germ-free mice or mice treated with broad spectrum antibiotics. In addition, the researchers found that CTLA-4–induced activation of splenic effector CD4+ T cells and tumor-infiltrating lymphocytes (TILs) was decreased in the latter cohorts, suggesting an impaired antitumor immune response in animals lacking the normal microbiota. Oral feeding of antibiotic-treated mice with certain bacterial species, such as B. thetaiotaomicron (Bt), B. fragilis (Bf), Burkholderia cepacia (Bc), or the combination of Bf and Bc, restored the anticancer response to anti–CTLA-4, whereas a number of other bacterial isolates failed to do so. Moreover, fecal microbial transplantation from patients with metastatic melanoma treated with the anti–CTLA-4 antibody ipilimumab into germ-free mice confirmed that the immunotherapy favored the outgrowth of Bf with anticancer properties. Last, intestinal reconstitution of antibiotic-treated animals with the combination of Bf and Bc did not increase but rather reduced histopathological signs of colitis induced by CTLA-4 blockade, suggesting that certain commensals could be real “anticancer-probiotics.”

The recent clinical success with anticancer immune therapies is hampered by the fact that durable responses are seen in only a subset of patients. It is still unclear what ultimately separates responders from nonresponders, but theoretical sources of interpatient heterogeneity likely include environmental differences, in addition to host- and tumor-specific genetic variability. The gut commensals play an important role in shaping individual systemic immune responses, and the study by Vétizou and colleagues suggests that manipulating the microbiota may modulate the efficacy and/or toxicity of cancer immunotherapies.

M. Vétizou et al., Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 10.1126/science.aad1329 (2015). [Abstract]

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