title: Toll-like Receptor 2 Activation Promotes Tumor Dendritic Cell Dysfunction by Regulating IL-6 and IL-10 Receptor Signaling.
abstract: Although dendritic cell (DC) dysfunction in cancer is a well-recognized consequence of cancer-associated inflammation that contributes to immune evasion, the mechanisms that drive this process remain elusive. Here, we show the critical importance of tumor-derived TLR2 ligands in the generation of immunosuppressive IL-10-producing human and mouse DCs. TLR2 ligation induced two parallel synergistic processes that converged to activate STAT3: stimulation of autocrine IL-6 and IL-10 and upregulation of their respective cell surface receptors, which lowered the STAT3 activation threshold. We identified versican as a soluble tumor-derived factor that activates TLR2 in DCs. TLR2 blockade in vivo improved intra-tumor DC immunogenicity and enhanced the efficacy of immunotherapy. Our findings provide a basis for understanding the molecular mechanisms of DC dysfunction in cancer and identify TLR2 as a relevant therapeutic target to improve cancer immunotherapy.
authors.affiliation: Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, ON M5G 2M9, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Tang
authors.affiliation: Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, ON M5G 2M9, Canada.
authors.forename: Jun
authors.initials: J
authors.lastname: Diao
authors.affiliation: Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, ON M5G 2M9, Canada.
authors.forename: Hongtao
authors.initials: H
authors.lastname: Gu
authors.affiliation: Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, ON M5G 2M9, Canada.
authors.forename: Ismat
authors.initials: I
authors.lastname: Khatri
authors.affiliation: Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, ON M5G 2M9, Canada.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, ON M5G 2M9, Canada; Department of Surgery, University of Toronto, Toronto, ON M5G 2N2, Canada. Electronic address: mark.cattral@uhn.ca.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Cattral
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D016753:Interleukin-10 / Q000276:immunology* / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000276:immunology* / Q000378:metabolism
chemical_list: C508609:IL10 protein, human; D015850:Interleukin-6; D051195:Toll-Like Receptor 2; D016753:Interleukin-10