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
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.
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Citation: Immunity. 2014 Nov 20;41(5):830-42. doi: 10.1016/j.immuni.2014.10.017. Link to article on publisher's site
Woo, Seng-Ryong; Fuertes, Mercedes B.; Corrales, Leticia; Spranger, Stefani; Furdyna, Michael J.; Leung, Michael Y. K.; Duggan, Ryan; Wang, Ying; Barber, Glen N.; Fitzgerald, Katherine A.; Alegre, Maria-Luisa; and Gajewski, Thomas F., "STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors" (2014). Infectious Diseases and Immunology Publications and Presentations. 193.