Tumor-Derived cGAMP Triggers a STING-Mediated Interferon Response in Non-tumor Cells to Activate the NK Cell Response

Detection of cytosolic DNA by the enzyme cGAS triggers the production of cGAMP, a second messenger that binds and activates the adaptor protein STING, which leads to interferon (IFN) production. Here, we found that in vivo natural killer (NK) cell killing of tumor cells, but not of normal cells, dep...

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Bibliographic Details
Published in:	Immunity (Cambridge, Mass.) Vol. 49; no. 4; pp. 754 - 763.e4
Main Authors:	Marcus, Assaf, Mao, Amy J., Lensink-Vasan, Monisha, Wang, LeeAnn, Vance, Russell E., Raulet, David H.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 16-10-2018 Elsevier Limited
Subjects:	Animal models Animals Cancer cancer immunology Cancer immunotherapy Cell activation Cell Line Cell Line, Tumor cGAMP cGAS Cytokines Deoxyribonucleic acid DNA DNA sensor Experiments Gene expression Gene Expression Regulation - immunology Humans Immunogenicity Immunotherapy Interferon Interferons - immunology Interferons - metabolism Killer Cells, Natural - immunology Killer Cells, Natural - metabolism Laboratories Ligands Lymphocytes Lymphocytes B Lymphoma Medical research Melanoma Membrane Proteins - genetics Membrane Proteins - immunology Membrane Proteins - metabolism Mice, Inbred C57BL Mice, Knockout Myeloid cells Natural killer cells Neoplasms - genetics Neoplasms - immunology Neoplasms - metabolism NK cells Nucleotides, Cyclic - immunology Nucleotides, Cyclic - metabolism Nucleotidyltransferases - genetics Nucleotidyltransferases - immunology Nucleotidyltransferases - metabolism Proteins Signal Transduction - immunology Software Statistical analysis STING Survival analysis T cell receptors Tumor cells tumor immunity Tumors β-Interferon United States > US natural killer cells NK cells cGAMP 3ʹ 2ʹ cancer immunology cancer immunotherapy cGAS STING tumor immunity DNA sensor interferon
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Summary:	Detection of cytosolic DNA by the enzyme cGAS triggers the production of cGAMP, a second messenger that binds and activates the adaptor protein STING, which leads to interferon (IFN) production. Here, we found that in vivo natural killer (NK) cell killing of tumor cells, but not of normal cells, depends on STING expression in non-tumor cells. Experiments using transplantable tumor models in STING- and cGAS-deficient mice revealed that cGAS expression by tumor cells was critical for tumor rejection by NK cells. In contrast, cGAS expression by host cells was dispensable, suggesting that tumor-derived cGAMP is transferred to non-tumor cells, where it activates STING. cGAMP administration triggered STING activation and IFN-β production in myeloid cells and B cells but not NK cells. Our results reveal that the anti-tumor response of NK cells critically depends on the cytosolic DNA sensing pathway, similar to its role in defense against pathogens, and identify tumor-derived cGAMP as a major determinant of tumor immunogenicity with implications for cancer immunotherapy. [Display omitted] •Sting−/− mice, but not Cgas−/− mice, fail to mount optimal NK cell anti-tumor responses•Cgas−/− tumor cells are defective in inducing anti-tumor responses by NK cells•cGAS is constitutively active in tumor cells but not in untransformed cells•cGAMP is transferred from tumor cells to other cells in the TME to activate STING Marcus et al. find that cGAMP produced by tumor cells triggers the activation of the STING pathway in immune cells within the tumor microenvironment. This leads to interferon production by these cells, which in turn activates NK cell anti-tumor immunity.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 A.M., A.M.J, M.L.V, and L.W conducted the experiments and A.M., R.E.V and D.H.R designed the experiments and wrote the paper. Author contributions
ISSN:	1074-7613 1097-4180
DOI:	10.1016/j.immuni.2018.09.016