Cancer-Cell-Intrinsic cGAS Expression Mediates Tumor Immunogenicity

Abstract

Summary: 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. : Schadt et al. show that cancer-cell-derived cGAMP is transferred to tumor-associated myeloid cells. Here, cGAMP activates STING and induces production of type I interferon. This promotes infiltration of protective CD8+ T cells and improves survival as well as response to therapy. Keywords: cGAMP, cGAS, STING, gap junctions, cancer, CD8+ T cells, type I IFN, chemotherapy, radiotherapy, immunotherapy