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.

• Klíčová slova
• CD8(+) T cells, STING, cGAMP, cGAS, cancer, chemotherapy, gap junctions, immunotherapy, radiotherapy, type I IFN,
• MeSH
• CD8-pozitivní T-lymfocyty imunologie   MeSH
• dendritické buňky metabolismus   MeSH
• imunoterapie MeSH
• interferon typ I metabolismus   MeSH
• lidé MeSH
• membránové proteiny MeSH
• mikrosatelitní repetice genetika   MeSH
• myši inbrední C57BL MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   imunologie   patologie   MeSH
• nukleotidy cyklické metabolismus   MeSH
• nukleotidyltransferasy metabolismus   MeSH
• poškození DNA MeSH
• progrese nemoci MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cGAS protein, human MeSH Prohlížeč
• cGAS protein, mouse MeSH Prohlížeč
• cyclic guanosine monophosphate-adenosine monophosphate MeSH Prohlížeč
• interferon typ I MeSH
• membránové proteiny MeSH
• nukleotidy cyklické MeSH
• nukleotidyltransferasy MeSH
• Sting1 protein, mouse MeSH Prohlížeč