Cancer-Cell-Intrinsic cGAS Expression Mediates Tumor Immunogenicity

0522837 - ÚMG 2020 RIV US eng J - Článek v odborném periodiku
Schadt, L. - Sparano, C. - Schweiger, N. A. - Silina, K. - Cecconi, V. - Lucchiari, G. - Yagita, H. - Guggisberg, E. - Saba, S. - Naščáková, Zuzana - Barchet, W. - van den Broek, M.
Cancer-Cell-Intrinsic cGAS Expression Mediates Tumor Immunogenicity.
Cell Reports. Roč. 29, č. 5 (2019), s. 1236-+. ISSN 2211-1247. E-ISSN 2211-1247
Grant CEP: GA ČR GA17-02080S
Institucionální podpora: RVO:68378050
Klíčová slova: cyclic gmp-amp * cytosolic dna sensor * i interferon * dendritic cells * immune cells * innate * antitumor * promotes * 2nd-messenger * activation
Obor OECD: Cell biology
Impakt faktor: 8.109, rok: 2019
Způsob publikování: Open access
https://www.cell.com/cell-reports/fulltext/S2211-1247(19)31262-8?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124719312628%3Fshowall%3Dtrue

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 cyto-plasmicDNA, they rarely producetype I IFNspontaneously. 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 geno-toxic treatments and immunotherapy. Thus, cancer-cell-derived cGAMPis 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.
Trvalý link: http://hdl.handle.net/11104/0307262