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Cancer-Cell-Intrinsic cGAS Expression Mediates Tumor Immunogenicity

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Schadt, Linda, Sparano, Colin, Schweiger, Nicole Angelika, Silina, Karina, Cecconi, Virginia, Lucchiari, Giulia, Yagita, Hideo, Guggisberg, Emilien, Saba, Sascha, Nascakova, Zuzana, Barchet, Winfried, van den Broek, Maries·2019·Cell Reports

DOI 10.1016/j.celrep.2019.09.065

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Abstract

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.

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See all 298

Authors: Schadt, L., Sparano, C., Schweiger, N. A., Silina, K., Cecconi, V., Lucchiari, G., Yagita, H., Guggisberg, E., Saba, S., Nascakova, Z., Barchet, W., & van den Broek, M.
Venue: Cell Reports
Publisher: Elsevier BV
Published: 2019-10
Volume: 29
Issue: 5
Pages: 1236-1248.e7
ISSN: 2211-1247 (ISSN-L)
DOI: 10.1016/j.celrep.2019.09.065
OpenAlex: W2982425966
Cited by: 298
References: 66
FWCI: 11.46
Type: journal article
Language: en
Open access: gold

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Cancer-Cell-Intrinsic cGAS Expression Mediates Tumor Immunogenicity

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Record

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Data sources