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Immunity. 2018 Oct 16;49(4):754-763.e4. doi: 10.1016/j.immuni.2018.09.016.

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

Author information

1
Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
2
Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Cancer Research Laboratory, University of California, Berkeley, Berkeley, CA 94720, USA; Immunotherapeutics and Vaccine Research Initiative, University of California, Berkeley, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: rvance@berkeley.edu.
3
Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Cancer Research Laboratory, University of California, Berkeley, Berkeley, CA 94720, USA; Immunotherapeutics and Vaccine Research Initiative, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: raulet@berkeley.edu.

Abstract

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.

KEYWORDS:

-cGAMP; 2ʹ; 3ʹ; DNA sensor; NK cells; STING; cGAS; cancer immunology; cancer immunotherapy; interferon; natural killer cells; tumor immunity

Comment in

PMID:
30332631
PMCID:
PMC6488306
[Available on 2019-10-16]
DOI:
10.1016/j.immuni.2018.09.016
[Indexed for MEDLINE]

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