MICROBIAL DRIVEN TLR5-DEPENDENT SIGNALING GOVERNS DISTAL MALIGNANT PROGRESSION THROUGH TUMOR-PROMOTING INFLAMMATION

• Published in: Cancer cell Vol. 27; no. 1; pp. 27 - 40
• Main Authors: Rutkowski, Melanie R., Stephen, Tom L., Svoronos, Nikolaos, Allegrezza, Michael J., Tesone, Amelia J., Perales-Puchalt, Alfredo, Brencicova, Eva, Escovar-Fadul, Ximena, Nguyen, Jenny M., Cadungog, Mark G., Zhang, Rugang, Salatino, Mariana, Tchou, Julia, Rabinovich, Gabriel A., Conejo-Garcia, Jose R.
• Format: Journal Article
• Language: English
• Published: 18.12.2014
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2014.11.009

The dominant TLR5 R392X polymorphism abrogates flagellin responses in >7% of humans. We report that TLR5-dependent commensal bacteria drive malignant progression at extra-mucosal locations by increasing systemic IL-6, which drives mobilization of myeloid derived suppressor cells (MDSCs). Mechanistically, expanded granulocytic MDSCs cause γδ lymphocytes in TLR5-responsive 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 mice, but only accelerates malignant progression in IL-6-unresponsive tumors. Importantly, depletion of commensal bacteria abrogates 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.