Cancer-Cell-Intrinsic cGAS Expression Mediates Tumor Immunogenicity.

Autor:	Schadt L; Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland., Sparano C; Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland., Schweiger NA; Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland., Silina K; Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland., Cecconi V; Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland., Lucchiari G; Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland., Yagita H; Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan., Guggisberg E; Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland., Saba S; Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland., Nascakova Z; Institute of Molecular Genetics of the ASCR, v. v. i., Videnska 1083, 142 20 Prague, Czech Republic., Barchet W; Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital and University of Bonn, Sigmund-Freud-Strasse 25, 35127 Bonn, Germany., van den Broek M; Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland. Electronic address: vandenbroek@immunology.uzh.ch.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2019 Oct 29; Vol. 29 (5), pp. 1236-1248.e7.
DOI:	10.1016/j.celrep.2019.09.065
Abstrakt:	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. (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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