STING-Dependent Cytosolic DNA Sensing Mediates Innate Immune Recognition of Immunogenic Tumors

• Published in: Immunity (Cambridge, Mass.) Vol. 41; no. 5; pp. 830 - 842
• Main Authors: 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, Gajewski, Thomas F.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20-11-2014; Elsevier Limited
• Subjects: Adaptive Immunity; Adaptor Proteins, Signal Transducing - genetics; Adoptive Transfer; Animals; Antigen-Presenting Cells - cytology; Antigen-Presenting Cells - immunology; Antigens; Cancer; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Cell Proliferation; Data analysis; Defects; Dendritic Cells - immunology; Deoxyribonucleic acid; DNA; DNA - immunology; Flow cytometry; Gene expression; Immune system; Immunity, Innate; Immunotherapy; Interferon Regulatory Factor-3 - genetics; Interferon-beta - biosynthesis; Kinases; Lymphocyte Activation - immunology; Lymphocytes; Melanoma; Melanoma, Experimental - immunology; Membrane Proteins - genetics; Membrane Proteins - immunology; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Differentiation Factor 88 - genetics; Nucleotidyltransferases; Peptides; Proteins; Receptors, Antigen, T-Cell - immunology; Receptors, Purinergic P2X7 - genetics; Software; Statistical analysis; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 9 - genetics; Tumor Microenvironment - immunology; Tumors
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2014.10.017

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-β 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-β 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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•Spontaneous T cell responses against tumors require the host STING pathway in vivo•Tumor-derived DNA can induce type I interferon production via STING•Tumor DNA can be identified in host APCs in the tumor microenvironment in vivo
The tumor-derived factors and host innate immune pathways that activate T cell responses against cancer are unclear. Gajewski and colleagues show a requirement for STING-dependent cytosolic DNA sensing in this process, via a mechanism associated with acquisition of tumor cell DNA by antigen-presenting cells.