Effect of Cyclophosphamide Mediated by Gut Microflora

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In a study reported in Science, Viaud and colleagues showed that the antitumor activity of cyclophosphamide is dependent on the effect of this agent on gut microflora.

In mouse studies, the investigators found that cyclophosphamide altered the composition of microbiota in the small intestine, inducing translocation of select Gram-positive organisms into secondary lymphoid organs. This drove a conversion of splenic-naive CD4-positive T cells into a predominance of “pathogenic” TH17 (pTH17) cells, which share characteristics of TH1 cells (nuclear expression of transcription factor T-bet, cytoplasmic expression of IFN-gamma, and surface exposure of the chemokine receptor CXCR3) and TH17 cells (expression of ROR-gamma-t, interleukin [IL]-17 and CCR6).

This conversion into IL-17–producing cells was not observed in the absence of the gut microbiota. IL-17 release by stimulated splenocytes occurred in specific-pathogen–free mice but not in germ-free mice and was suppressed in mice receiving broad-spectrum antibiotic treatment or treatment with vancomycin, which is specific for Gram-positive bacteria.

The antitumor effects of cyclophosphamide were reduced by broad-spectrum antibiotic treatment in mice with P815 mastocytomas and reduced in germ-free mice vs specific-pathogen–free mice with MCA205 sarcomas. Vancomycin treatment reduced the tumor inhibitory effects of cyclophosphamide compared with treatment with colisitin, which acts against Gram-negative bacteria.

Vancomycin inhibited the efficacy of a cyclophosphamide-based regimen in a transgenic model of autochthonous lung carcinogenesis driven by oncogenic KRAS coupled to conditional p53 deletion. Further, vancomycin prevented cyclophosphamide-induced splenic accumulation of pTH17 cells and reduced the frequencies of tumor-infiltrating CD3-positive T cells and TH1 cells.

The investigators concluded, “Although much of the detailed molecular mechanisms governing the complex interplay between epithelial cells, gut microbiota, and intestinal immunity remain to be deciphered, the present study unveils the unsuspected impact of the intestinal flora on chemotherapy-elicited anticancer immune responses. Our data underscore new risks associated with antibiotic medication during cancer treatments, as well as the potential therapeutic utility of manipulating the gut microbiota.”

Viaud S, et al: Science 342:971-976, 2013.