STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors

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 sp...

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Veröffentlicht in:	Immunity (Cambridge, Mass.) Jg. 41; H. 5; S. 830
Hauptverfasser:	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
Sprache:	Englisch
Veröffentlicht:	United States 20.11.2014
Schlagworte:	Adaptive Immunity Adaptor Proteins, Signal Transducing - genetics Adoptive Transfer Animals Antigen-Presenting Cells - cytology Antigen-Presenting Cells - immunology CD8-Positive T-Lymphocytes - immunology Cell Line, Tumor Cell Proliferation Dendritic Cells - immunology DNA - immunology Immunity, Innate Interferon Regulatory Factor-3 - genetics Interferon-beta - biosynthesis Lymphocyte Activation - immunology Melanoma, Experimental - immunology Membrane Proteins - genetics Membrane Proteins - immunology Mice Mice, Inbred C57BL Mice, Knockout Myeloid Differentiation Factor 88 - genetics Nucleotidyltransferases Receptors, Antigen, T-Cell - immunology Receptors, Purinergic P2X7 - genetics Toll-Like Receptor 4 - genetics Toll-Like Receptor 9 - genetics Tumor Microenvironment - immunology
ISSN:	1097-4180, 1097-4180
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Zusammenfassung:	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.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1097-4180 1097-4180
DOI:	10.1016/j.immuni.2014.10.017