title: Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1.
abstract: The mechanisms by which tumor microenvironments modulate nucleic acid-mediated innate immunity remain unknown. Here we identify the receptor TIM-3 as key in circumventing the stimulatory effects of nucleic acids in tumor immunity. Tumor-associated dendritic cells (DCs) in mouse tumors and patients with cancer had high expression of TIM-3. DC-derived TIM-3 suppressed innate immune responses through the recognition of nucleic acids by Toll-like receptors and cytosolic sensors via a galectin-9-independent mechanism. In contrast, TIM-3 interacted with the alarmin HMGB1 to interfere with the recruitment of nucleic acids into DC endosomes and attenuated the therapeutic efficacy of DNA vaccination and chemotherapy by diminishing the immunogenicity of nucleic acids released from dying tumor cells. Our findings define a mechanism whereby tumor microenvironments suppress antitumor immunity mediated by nucleic acids.
authors: Research Center for Infection-Associated Cancer, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
authors: Shigeki
authors: S
authors: Chiba
authors: Muhammad
authors: M
authors: Baghdadi
authors: Hisaya
authors: H
authors: Akiba
authors: Hironori
authors: H
authors: Yoshiyama
authors: Ichiro
authors: I
authors: Kinoshita
authors: Hirotoshi
authors: H
authors: Dosaka-Akita
authors: Yoichiro
authors: Y
authors: Fujioka
authors: Yusuke
authors: Y
authors: Ohba
authors: Jacob V
authors: JV
authors: Gorman
authors: John D
authors: JD
authors: Colgan
authors: Mitsuomi
authors: M
authors: Hirashima
authors: Toshimitsu
authors: T
authors: Uede
authors: Akinori
authors: A
authors: Takaoka
authors: Hideo
authors: H
authors: Yagita
authors: Masahisa
authors: M
authors: Jinushi
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D024243:HMGB1 Protein / Q000276:immunology* / Q000378:metabolism; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D007113:Immunity, Innate; D015151:Immunoblotting; D007157:Immunologic Surveillance / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism; D009696:Nucleic Acids / Q000276:immunology*; D051192:Receptors, Pattern Recognition / Q000276:immunology; D011991:Receptors, Virus / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D024243:HMGB1 Protein; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D009696:Nucleic Acids; D051192:Receptors, Pattern Recognition; D011991:Receptors, Virus