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

• DOI: 10.1016/j.ccell.2014.11.009
• Publication Date: 2014-12-20T01:51:43Z
• Authors: Melanie R. Rutkowski; Tom L. Stephen; Nikolaos Svoronos; Michael J. Allegr...; Amelia J. Tesone; Alfredo Perales-P...; Eva Brencicova; Ximena Escovar-Fadul; Jenny M. Nguyen; Mark G. Cadungog; Rugang Zhang; Mariana Salatino; Julia Tchou; Gabriel A. Rabino...; Jose R. Conejo-Ga...
• Keywords: Cancer Research; Galectin 1; Molecular Sequence Data; Mice, Transgenic; Polymorphism, Single Nucleotide; Mice; Cell Line, Tumor; Neoplasms; https://purl.org/becyt/ford/3.1; Animals; Humans; https://purl.org/becyt/ford/3; Tlr5; Cells, Cultured; Tumor; Bacteria; Interleukin-6; Microbiota; Interleukin-17; Cell Biology; 3. Good health; Gene Expression Regulation, Neoplastic; Mice, Inbred C57BL; Toll-Like Receptor 5; Oncology; Myeloid-Derived Suppresor Cells; Neoplasm Transplantation; Signal Transduction

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.