Microbial driven TLR5-dependent signaling modulates distal malignant progression through tumor-promoting inflammation (MUC4P.828)

The dominant R392X TLR5 polymorphism abrogates flagellin responses in >7% of humans. We report that TLR5 recognition of commensal bacteria at intestinal surfaces influences malignant progression at distal (extra-mucosal) locations through the initiation of tumor-promoting inflammation. In TLR5-responsive mice, IL-6 is up-regulated through an autocrine loop in IL-6 reactive tumor cells, resulting in increased mobilization of MDSC and augmented tumor growth, compared to TLR5-deficient controls. In contrast, TLR5-deficient mice systemically up-regulate IL-17, which augments tumor growth only in the presence of IL-6 unresponsive tumors. Notably, differences in tumor growth are completely abrogated following depletion of commensal bacteria. Most importantly, similar differences in inflammation and malignant progression are recapitulated in TLR5-responsive/unresponsive patients with extra-mucosal tumors. Our results demonstrate that TLR5 signaling at mucosal surfaces, which is dependent upon commensal microbiota, significantly influences tumor progression at extra-mucosal locations through systemic tumor-promoting inflammation. These results have implications for the large proportion of individuals that harbor the common genetic polymorphism in TLR5 and demonstrate that the systemic response to tumors outside of the intestines is in part mediated through TLR5-signaling.