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

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

Immunity (2018-10-18)
Assaf Marcus, Amy J Mao, Monisha Lensink-Vasan, LeeAnn Wang, Russell E Vance, David H Raulet
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Deoxyribonucleic acid sodium salt from herring testes, Type XIV
Sigma-Aldrich
Polybrene Infection / Transfection Reagent, A highly efficient method of gene transfer into mammalian cells leveraging infection with retroviral vectors.
Sigma-Aldrich
Anti- STING, clone 41 Antibody, clone 41, 0.5 mg/mL, from rat