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: Seng-Ryong Woo, Mercedes B Fuertes, Leticia Corrales, Stefani Spranger, Michael J Furdyna, Michael Y K Leung, Ryan Duggan, Ying Wang, Glen N Barber, Katherine A Fitzgerald, Maria-Luisa Alegre, Thomas F Gajewski
• Journal: Immunity (Immunity) Vol. 41 Issue 5 Pg. 830-42 (Nov 20 2014) ISSN: 1097-4180 [Electronic] United States
• PMID: 25517615 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Adaptor Proteins, Signal Transducing
• IPS-1 protein, mouse
• Interferon Regulatory Factor-3
• Irf3 protein, mouse
• Membrane Proteins
• Myd88 protein, mouse
• Myeloid Differentiation Factor 88
• Receptors, Antigen, T-Cell
• Receptors, Purinergic P2X7
• Sting1 protein, mouse
• Tlr4 protein, mouse
• Tlr9 protein, mouse
• Toll-Like Receptor 4
• Toll-Like Receptor 9
• Interferon-beta
• DNA
• Nucleotidyltransferases
• cGAS protein, mouse

Topics

• Adaptive Immunity
• Adaptor Proteins, Signal Transducing (genetics)
• Adoptive Transfer
• Animals
• Antigen-Presenting Cells (cytology, immunology)
• CD8-Positive T-Lymphocytes (immunology)
• Cell Line, Tumor
• Cell Proliferation
• DNA (immunology)
• Dendritic Cells (immunology)
• Immunity, Innate
• Interferon Regulatory Factor-3 (genetics)
• Interferon-beta (biosynthesis)
• Lymphocyte Activation (immunology)
• Melanoma, Experimental (immunology)
• Membrane Proteins (genetics, 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)