Cancer-Cell-Intrinsic cGAS Expression Mediates Tumor Immunogenicity

Publication date: 29 October 2019Source: Cell Reports, Volume 29, Issue 5Author(s): Linda Schadt, Colin Sparano, Nicole Angelika Schweiger, Karina Silina, Virginia Cecconi, Giulia Lucchiari, Hideo Yagita, Emilien Guggisberg, Sascha Saba, Zuzana Nascakova, Winfried Barchet, Maries van den BroekSummarySensing 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 c...

Source: Cell Reports - October 31, 2019 Category: Cytology Source Type: research