
Microbially driven TLR5-dependent signaling governs distal malignant progression through tumor-promoting inflammation.
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.
Duke Scholars
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Related Subject Headings
- Toll-Like Receptor 5
- Signal Transduction
- Polymorphism, Single Nucleotide
- Oncology & Carcinogenesis
- Neoplasms
- Neoplasm Transplantation
- Molecular Sequence Data
- Microbiota
- Mice, Transgenic
- Mice, Inbred C57BL
Citation

Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Toll-Like Receptor 5
- Signal Transduction
- Polymorphism, Single Nucleotide
- Oncology & Carcinogenesis
- Neoplasms
- Neoplasm Transplantation
- Molecular Sequence Data
- Microbiota
- Mice, Transgenic
- Mice, Inbred C57BL