[PDF][PDF] Microbially driven TLR5-dependent signaling governs distal malignant progression through tumor-promoting inflammation

MR Rutkowski, TL Stephen, N Svoronos, MJ Allegrezza… - Cancer cell, 2015 - cell.com
MR Rutkowski, TL Stephen, N Svoronos, MJ Allegrezza, AJ Tesone, A Perales-Puchalt
Cancer cell, 2015cell.com
Summary 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 …
Summary
The dominant TLR5R392X 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.
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