title: TLR9 signaling in the tumor microenvironment initiates cancer recurrence after radiotherapy.
abstract: 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.
authors.affiliation: Authors' Affiliations: Departments of Cancer Immunotherapeutics and Tumor Immunology, Medical Oncology, and Pathology; Bioinformatics Core Facility; DNA/RNA Synthesis Core Facility; Division of Translational Vaccine Research; Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute at City of Hope, Duarte, California; and Medical Biotechnology, University of Medical Sciences, Poznan, Poland.
authors.forename: Chan
authors.initials: C
authors.lastname: Gao
authors.forename: Anna
authors.initials: A
authors.lastname: Kozlowska
authors.forename: Sergey
authors.initials: S
authors.lastname: Nechaev
authors.forename: Haiqing
authors.initials: H
authors.lastname: Li
authors.forename: Qifang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Dewan M S
authors.initials: DM
authors.lastname: Hossain
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Kowolik
authors.forename: Peiguo
authors.initials: P
authors.lastname: Chu
authors.forename: Piotr
authors.initials: P
authors.lastname: Swiderski
authors.forename: Don J
authors.initials: DJ
authors.lastname: Diamond
authors.forename: Sumanta K
authors.initials: SK
authors.lastname: Pal
authors.forename: Andrew
authors.initials: A
authors.lastname: Raubitschek
authors.forename: Marcin
authors.initials: M
authors.lastname: Kortylewski
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D003110:Colonic Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D015850:Interleukin-6 / Q000378:metabolism; D008546:Melanoma, Experimental / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D051217:Toll-Like Receptor 9 / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000235:genetics / Q000502:physiology; D001749:Urinary Bladder Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy
chemical_list: D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; C577686:interleukin-6, mouse