Abstract C285: TLR9 signaling in the tumor microenvironment initiates cancer recurrence after radiation therapy.

Recent studies suggested that cancer radiotherapy is potentially immunogenic. However, it is unclear why such effects rarely prevent tumor recurrence. Here, we uncover a novel Toll-like Receptor 9 (TLR9)-dependent mechanism initiating tumor regrowth after local radiotherapy. Systemic inhibition of TLR9, but not TLR4, delayed the recurrence of B16 melanoma, MB49 bladder, and CT26 colon cancers after localized, high dose tumor irradiation. We demonstrate that soluble factors present in the microenvironment of regressing tumors trigger TLR9 signaling in freshly recruited myeloid cells within four days after radiotherapy. The tumorigenic effects of TLR9 depended on rapid upregulation of IL-6 expression, which in turn resulted in downstream activation of Jak/STAT3 signaling in myeloid cells. By 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. To assess whether blocking STAT3 can correct the aberrant TLR9 signaling, we used mice with a myeloid cell-specific Stat3 gene ablation or we treated mice using CpG-Stat3 siRNA to target TLR9-positive cells. Both approaches confirmed that targeting STAT3 in myeloid cells abrogates TLR9-mediated cancer recurrence after radiation therapy. Our results suggest that combining localized tumor irradiation with myeloid cell-specific inhibition of TLR9/STAT3 signaling can generate new strategies for the elimination of radiation resistant cancers. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C285. Citation Format: Chan Gao. TLR9 signaling in the tumor microenvironment initiates cancer recurrence after radiation therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C285.