title: STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors.
abstract: Ionizing radiation-mediated tumor regression depends on type I interferon (IFN) and the adaptive immune response, but several pathways control I IFN induction. Here, we demonstrate that adaptor protein STING, but not MyD88, is required for type I IFN-dependent antitumor effects of radiation. In dendritic cells (DCs), STING was required for IFN-? induction in response to irradiated-tumor cells. The cytosolic DNA sensor cyclic GMP-AMP (cGAMP) synthase (cGAS) mediated sensing of irradiated-tumor cells in DCs. Moreover, STING was essential for radiation-induced adaptive immune responses, which relied on type I IFN signaling on DCs. Exogenous IFN-? treatment rescued the cross-priming by cGAS or STING-deficient DCs. Accordingly, activation of STING by a second messenger cGAMP administration enhanced antitumor immunity induced by radiation. Thus radiation-mediated antitumor immunity in immunogenic tumors requires a functional cytosolic DNA-sensing pathway and suggests that cGAMP treatment might provide a new strategy to improve radiotherapy.
authors.affiliation: Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA; The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Liufu
authors.initials: L
authors.lastname: Deng
authors.affiliation: Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA; The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Liang
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Xuanming
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA; The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Byron
authors.initials: B
authors.lastname: Burnette
authors.affiliation: Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA; The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Arina
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Li
authors.affiliation: Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA; The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Helena
authors.initials: H
authors.lastname: Mauceri
authors.affiliation: Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA; The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Beckett
authors.affiliation: Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA; The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Darga
authors.affiliation: Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Xiaona
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Gajewski
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Zhijian J
authors.initials: ZJ
authors.lastname: Chen
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL 60637, USA; The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL 60637, USA. Electronic address: yfu@uchicago.edu.
authors.forename: Yang-Xin
authors.initials: YX
authors.lastname: Fu
authors.affiliation: Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA; The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL 60637, USA. Electronic address: rrw@radonc.uchicago.edu.
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Weichselbaum
mesh_terms: D056704:Adaptive Immunity; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D045142:Cross-Priming / Q000276:immunology; D004247:DNA / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D007113:Immunity, Innate; D016899:Interferon-beta / Q000096:biosynthesis / Q000276:immunology / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D009369:Neoplasms / Q000276:immunology / Q000532:radiotherapy*; D009712:Nucleotides, Cyclic / Q000494:pharmacology; D009713:Nucleotidyltransferases / Q000276:immunology*; D034622:RNA Interference; D034741:RNA, Small Interfering; D011839:Radiation, Ionizing; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D044004:Xanthones / Q000494:pharmacology; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000970:Antineoplastic Agents; D004247:DNA; D016899:Interferon-beta; D008565:Membrane Proteins; D053594:Myeloid Differentiation Factor 88; D009712:Nucleotides, Cyclic; D009713:Nucleotidyltransferases; D034741:RNA, Small Interfering; D053633:Receptor, Interferon alpha-beta; D044004:Xanthones; C508032:Ifnar1 protein, mouse; C507780:Myd88 protein, mouse; C530855:Sting1 protein, mouse; D000099197:STING Protein; C476286:Ticam1 protein, mouse; C584311:cyclic guanosine monophosphate-adenosine monophosphate; C066668:vadimezan; C578391:cGAS protein, mouse; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase