期刊
CELL REPORTS
卷 29, 期 5, 页码 1236-+出版社
CELL PRESS
DOI: 10.1016/j.celrep.2019.09.065
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资金
- Swiss National Science Foundation (SNSF)
- Swiss Cancer League (Oncosuisse)
- Science Foundation for Oncology (SFO)
- Hartmann-Muller Foundation
- Helmut-Horten Foundation
- University Research Priority Program (URPP) Translational Cancer Research
- Czech Science Foundation [17-02080S]
Sensing of cytoplasmic DNA by cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) results in production of the dinucleotide cGAMP and consecutive activation of stimulator of interferon genes (STING) followed by production of type I interferon (IFN). Although cancer cells contain supra-normal concentrations of cyto-plasmicDNA, they rarely producetype I IFNspontaneously. This suggests that defects in the DNA-sensing pathway may serve as an immune escape mechanism. We find that cancer cells produce cGAMP that is transferred via gap junctions to tumor-associated dendritic cells (DCs) and macrophages, which respond by producing type I IFN in situ. Cancer-cell-intrinsic expression of cGAS, but not STING, promotes infiltration by effector CD8(+) T cells and consequently results in prolonged survival. Furthermore, cGAS-expressing cancers respond better to geno-toxic treatments and immunotherapy. Thus, cancer-cell-derived cGAMPis crucial to protective anti-tumor CD8(+) T cell immunity. Consequently, cancer-cell-intrinsic expression of cGAS determines tumor immunogenicity and makes tumors hot. These findings are relevant for genotoxic and immune therapies for cancer.
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