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Microbially Driven TLR5-Dependent Signaling Governs Distal Malignant Progression through Tumor-Promoting Inflammation

2014; Cell Press; Volume: 27; Issue: 1 Linguagem: Inglês

10.1016/j.ccell.2014.11.009

1878-3686

Melanie R. Rutkowski, Tom L. Stephen, Nikolaos Svoronos, Michael J. Allegrezza, Amelia J. Tesone, Alfredo Perales‐Puchalt, Eva Brencicova, Ximena Escovar-Fadul, Jenny Nguyen, Mark G. Cadungog, Rugang Zhang, Mariana Salatino, Julia Tchou, Gabriel A. Rabinovich, José R. Conejo-García,

Helicobacter pylori-related gastroenterology studies

The dominant TLR5(R392X) polymorphism abrogates flagellin responses in >7% of humans. We report that TLR5-dependent commensal bacteria drive malignant progression at extramucosal 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 antitumor immunity and accelerating malignant progression. In contrast, IL-17 is consistently upregulated 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, antitumor immunity, and the clinical outcome of cancer patients are influenced by a common TLR5 polymorphism.