STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors
Department of Medicine, Division of Infectious Disease & Immunology
Adaptive Immunity; Adaptor Proteins, Signal Transducing; Adoptive Transfer; Animals; Antigen-Presenting Cells; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Cell Proliferation; DNA; Dendritic Cells; Immunity, Innate; Interferon Regulatory Factor-3; Interferon-beta; Lymphocyte Activation; Melanoma, Experimental; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Differentiation Factor 88; Nucleotidyltransferases; Receptors, Antigen, T-Cell; Receptors, Purinergic P2X7; Toll-Like Receptor 4; Toll-Like Receptor 9; Tumor Microenvironment
Immunity | Immunology and Infectious Disease | Immunology of Infectious Disease | Infectious Disease
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.
DOI of Published Version
Immunity. 2014 Nov 20;41(5):830-42. doi: 10.1016/j.immuni.2014.10.017. Link to article on publisher's site
Woo S, Fuertes MB, Corrales L, Spranger S, Furdyna MJ, Leung MY, Duggan R, Wang Y, Barber GN, Fitzgerald KA, Alegre M, Gajewski TF. (2014). STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Infectious Diseases and Immunology Publications. https://doi.org/10.1016/j.immuni.2014.10.017. Retrieved from https://escholarship.umassmed.edu/infdis_pp/193