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Cancer-Cell-Intrinsic cGAS Expression Mediates Tumor Immunogenicity

2019; Cell Press; Volume: 29; Issue: 5 Linguagem: Inglês

10.1016/j.celrep.2019.09.065

2639-1856

Linda Schadt, Colin Sparano, Nicole Angelika Schweiger, Karīna Siliņa, Virginia Cecconi, Giulia Lucchiari, Hideo Yagita∥, Emilien Guggisberg, Sascha Saba, Zuzana Naščáková, Winfried Barchet, Maries van den Broek,

Immune Response and Inflammation

Highlights•cGAS in cancer and STING in host cells are minimal requirements to activate CD8+ T cells•Cancer cells transfer cGAMP to myeloid cells in the TME that make STING-dependent IFN-I•Cancer-cell-intrinsic cGAS improves tumor immunogenicity and response to therapySummarySensing 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.Graphical abstract