TLR9 signaling in the tumor microenvironment initiates cancer recurrence after radiotherapy

Cancer Res. 2013 Dec 15;73(24):7211-21. doi: 10.1158/0008-5472.CAN-13-1314. Epub 2013 Oct 23.


Cancer radiotherapy may be immunogenic, but it is unclear why its immunogenic effects are rarely sufficient to prevent tumor recurrence. Here, we report a novel Toll-like receptor 9 (TLR9)-dependent mechanism that initiates tumor regrowth after local radiotherapy. Systemic inhibition of TLR9, but not TLR4, delayed tumor recurrence in mouse models of B16 melanoma, MB49 bladder cancer, and CT26 colon cancer after localized high-dose tumor irradiation. Soluble factors in the microenvironment of regressing tumors triggered TLR9 signaling in freshly recruited myeloid cells appearing within four days of radiotherapy. The tumorigenic effects of TLR9 depended on MyD88/NF-κB-mediated upregulation of interleukin (IL)-6 expression, which in turn resulted in downstream activation of Jak/STAT3 signaling in myeloid cells. In comparing global gene expression in wild-type, TLR9-, or STAT3-deficient myeloid cells derived from irradiated tumors, we identified a unique set of TLR9/STAT3-regulated genes involved in tumor-promoting inflammation and revascularization. Blocking STAT3 function by two myeloid-specific genetic strategies corrected TLR9-mediated cancer recurrence after radiotherapy. Our results suggest that combining localized tumor irradiation with myeloid cell-specific inhibition of TLR9/STAT3 signaling may help eliminate radioresistant cancers.

Publication types

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

MeSH terms

  • Animals
  • Cell Growth Processes / physiology
  • Colonic Neoplasms / blood supply
  • Colonic Neoplasms / metabolism*
  • Colonic Neoplasms / pathology
  • Colonic Neoplasms / radiotherapy
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • Interleukin-6 / metabolism
  • Melanoma, Experimental / blood supply
  • Melanoma, Experimental / metabolism*
  • Melanoma, Experimental / pathology
  • Melanoma, Experimental / radiotherapy
  • Mice
  • Mice, Transgenic
  • Myeloid Cells / metabolism
  • Myeloid Cells / pathology
  • Neoplasm Recurrence, Local / genetics
  • Neoplasm Recurrence, Local / metabolism*
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • Toll-Like Receptor 9 / metabolism*
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / physiology
  • Urinary Bladder Neoplasms / blood supply
  • Urinary Bladder Neoplasms / metabolism*
  • Urinary Bladder Neoplasms / pathology
  • Urinary Bladder Neoplasms / radiotherapy


  • Interleukin-6
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Tlr9 protein, mouse
  • Toll-Like Receptor 9
  • interleukin-6, mouse