title: cGAS is essential for the antitumor effect of immune checkpoint blockade.
abstract: cGMP-AMP (cGAMP) synthase (cGAS) is a cytosolic DNA sensor that activates innate immune responses. cGAS catalyzes the synthesis of cGAMP, which functions as a second messenger that binds and activates the adaptor protein STING to induce type I interferons (IFNs) and other immune modulatory molecules. Here we show that cGAS is indispensable for the antitumor effect of immune checkpoint blockade in mice. Wild-type, but not cGAS-deficient, mice exhibited slower growth of B16 melanomas in response to a PD-L1 antibody treatment. Consistently, intramuscular delivery of cGAMP inhibited melanoma growth and prolonged the survival of the tumor-bearing mice. The combination of cGAMP and PD-L1 antibody exerted stronger antitumor effects than did either treatment alone. cGAMP treatment activated dendritic cells and enhanced cross-presentation of tumor-associated antigens to CD8 T cells. These results indicate that activation of the cGAS pathway is important for intrinsic antitumor immunity and that cGAMP may be used directly for cancer immunotherapy.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148.
authors.forename: Shuiqing
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148.|Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148.
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148.|Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148.
authors.forename: Heping
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148.
authors.forename: Chuo
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148.|Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148.
authors.forename: Lijun
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148; Zhijian.Chen@UTSouthwestern.edu.|Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148.
authors.forename: Zhijian J
authors.initials: ZJ
authors.lastname: Chen
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D045142:Cross-Priming / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology*; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009712:Nucleotides, Cyclic / Q000008:administration & dosage / Q000276:immunology* / Q000494:pharmacology; D009713:Nucleotidyltransferases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016019:Survival Analysis; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D000906:Antibodies; D060890:B7-H1 Antigen; D009712:Nucleotides, Cyclic; D009713:Nucleotidyltransferases; C498919:Cd274 protein, mouse; C584311:cyclic guanosine monophosphate-adenosine monophosphate; C578391:cGAS protein, mouse; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
keywords: PD-L1; STING; cGAMP; cGAS; cancer