Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
Cell Rep. 2019 Oct 29;29(5):1236-1248.e7. doi: 10.1016/j.celrep.2019.09.065.
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 cytoplasmic DNA, they rarely produce type I IFN spontaneously. 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 genotoxic treatments and immunotherapy. Thus, cancer-cell-derived cGAMP is 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.
环状鸟苷酸-腺苷酸（cGAMP）合酶（cGAS）对细胞质 DNA 的感应导致二核苷酸 cGAMP 的产生，并随后激活干扰素基因刺激物（STING），继而产生 I 型干扰素（IFN）。尽管癌细胞含有超正常浓度的细胞质 DNA，但它们很少自发产生 I 型 IFN。这表明 DNA 感应途径的缺陷可能作为一种免疫逃避机制。我们发现癌细胞产生 cGAMP，它通过间隙连接转移到肿瘤相关的树突状细胞（DC）和巨噬细胞，这些细胞通过原位产生 I 型 IFN 作出反应。cGAS 在癌细胞中的表达而非 STING 的表达促进效应性 CD8 T 细胞的浸润，从而导致存活时间延长。此外，表达 cGAS 的癌症对细胞毒性治疗和免疫疗法的反应更好。因此，癌细胞衍生的 cGAMP 对于保护性抗肿瘤 CD8 T 细胞免疫至关重要。因此，cGAS 在癌细胞中的表达决定了肿瘤的免疫原性，并使肿瘤变得“热”。这些发现与癌症的细胞毒性和免疫治疗有关。
