0599767d
MICROBIAL DRIVEN TLR5-DEPENDENT SIGNALING GOVERNS DISTAL MALIGNANT PROGRESSION THROUGH TUMOR-PROMOTING INFLAMMATION
We show that TLR5 recognition of commensal bacteria results in elevated IL-6 levels during tumor progression, whereas in TLR5 non-responsive tumor-bearing mice, there is an increased systemic production of IL-17. Mechanistically, we demonstrate that TLR5 signaling is driving differential tumor-promoting inflammation, and the balance of IL-6 and IL-17 influences the outcome of malignant progression.
The dominant R392X TLR5 polymorphism abrogates flagellin responses in >7% of humans. We report that TLR5-dependent commensal bacteria drive malignant progression at (distal) extra-mucosal locations by promoting systemic IL-6 up-regulation, which drives MDSC mobilization. Mechanistically, expanded granulocytic MDSCs cause gd lymphocytes in TLR5+/+ tumors to secrete galectin-1, dampening anti-tumor immunity and accelerating malignant progression. In contrast, IL-17 is consistently up-regulated in TLR5-unresponsive tumor-bearing individuals, but only accelerates malignant progression in IL-6-unresponsive tumors. Importantly, depletion of commensal bacteria abrogates any TLR5-dependent differences in tumor growth. Contrasting differences in inflammatory cytokines and malignant evolution are recapitulated in TLR5-responsive/unresponsive ovarian and breast cancer patients. Therefore, inflammation, anti-tumor immunity and the clinical outcome of cancer patients are influenced by a common TLR5 polymorphism.