title: STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors.
abstract: Spontaneous T cell responses against tumors occur frequently and have prognostic value in patients. The mechanism of innate immune sensing of immunogenic tumors leading to adaptive T cell responses remains undefined, although type I interferons (IFNs) are implicated in this process. We found that spontaneous CD8(+) T cell priming against tumors was defective in mice lacking stimulator of interferon genes complex (STING), but not other innate signaling pathways, suggesting involvement of a cytosolic DNA sensing pathway. In vitro, IFN-? production and dendritic cell activation were triggered by tumor-cell-derived DNA, via cyclic-GMP-AMP synthase (cGAS), STING, and interferon regulatory factor 3 (IRF3). In the tumor microenvironment in vivo, tumor cell DNA was detected within host antigen-presenting cells, which correlated with STING pathway activation and IFN-? production. Our results demonstrate that a major mechanism for innate immune sensing of cancer occurs via the host STING pathway, with major implications for cancer immunotherapy.
authors.affiliation: Department of Pathology, The University of Chicago, 929 E57th Street GCIS W423H, Chicago, IL 60637, USA.
authors.forename: Seng-Ryong
authors.initials: SR
authors.lastname: Woo
authors.affiliation: Department of Pathology, The University of Chicago, 929 E57th Street GCIS W423H, Chicago, IL 60637, USA.
authors.forename: Mercedes B
authors.initials: MB
authors.lastname: Fuertes
authors.affiliation: Department of Pathology, The University of Chicago, 929 E57th Street GCIS W423H, Chicago, IL 60637, USA.
authors.forename: Leticia
authors.initials: L
authors.lastname: Corrales
authors.affiliation: Department of Pathology, The University of Chicago, 929 E57th Street GCIS W423H, Chicago, IL 60637, USA.
authors.forename: Stefani
authors.initials: S
authors.lastname: Spranger
authors.affiliation: Department of Pathology, The University of Chicago, 929 E57th Street GCIS W423H, Chicago, IL 60637, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Furdyna
authors.affiliation: Department of Pathology, The University of Chicago, 929 E57th Street GCIS W423H, Chicago, IL 60637, USA.
authors.forename: Michael Y K
authors.initials: MY
authors.lastname: Leung
authors.affiliation: Flow Cytometry Core Facility, The University of Chicago, 924 E57th Street r022, Chicago, IL 60637, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Duggan
authors.affiliation: Department of Medicine, The University of Chicago, 5841 South Maryland Avenue, MC6092, Chicago, IL 60637, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cell Biology, University of Miami, Rosenstiel Medical Science Building, 4th Floor 1600 N.W. 10th Avenue, Miami, FL 33136, USA.
authors.forename: Glen N
authors.initials: GN
authors.lastname: Barber
authors.affiliation: Department of Infectious Diseases and Immunology, University of Massachusetts, 364 Plantation Street, LRB, Worcester, MA 01605, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.affiliation: Department of Medicine, The University of Chicago, 5841 South Maryland Avenue, MC6092, Chicago, IL 60637, USA.
authors.forename: Maria-Luisa
authors.initials: ML
authors.lastname: Alegre
authors.affiliation: Department of Pathology, The University of Chicago, 929 E57th Street GCIS W423H, Chicago, IL 60637, USA; Department of Medicine, The University of Chicago, 5841 South Maryland Avenue, MC6092, Chicago, IL 60637, USA. Electronic address: tgajewsk@medicine.bsd.uchicago.edu.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Gajewski
mesh_terms: D056704:Adaptive Immunity; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D019264:Adoptive Transfer; D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004247:DNA / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000235:genetics; D016899:Interferon-beta / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D009713:Nucleotidyltransferases; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D058486:Receptors, Purinergic P2X7 / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics; D051217:Toll-Like Receptor 9 / Q000235:genetics; D059016:Tumor Microenvironment / Q000276:immunology; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004247:DNA; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta; D008565:Membrane Proteins; D053594:Myeloid Differentiation Factor 88; D009713:Nucleotidyltransferases; D011948:Receptors, Antigen, T-Cell; D058486:Receptors, Purinergic P2X7; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; C512612:MAVS protein, mouse; C494233:Irf3 protein, mouse; C507780:Myd88 protein, mouse; C530855:Sting1 protein, mouse; D000099197:STING Protein; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse; C578391:cGAS protein, mouse; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase