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

Cancer Cell. 2015 Jan 12;27(1):27-40. doi: 10.1016/j.ccell.2014.11.009. Epub 2014 Dec 18.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cells, Cultured
  • Galectin 1 / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Interleukin-17 / metabolism*
  • Interleukin-6 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microbiota*
  • Molecular Sequence Data
  • Neoplasm Transplantation
  • Neoplasms / immunology*
  • Neoplasms / pathology*
  • Polymorphism, Single Nucleotide
  • Signal Transduction
  • Toll-Like Receptor 5 / genetics*
  • Toll-Like Receptor 5 / metabolism*

Substances

  • Galectin 1
  • Interleukin-17
  • Interleukin-6
  • Toll-Like Receptor 5

Associated data

  • SRA/SRP045910