cGAS is essential for the antitumor effect of immune checkpoint blockade

Hua Wang; Shuiqing Hu; Xiang Chen; Heping Shi; Chuo Chen; Lijun Sun; Zhijian J Chen

doi:10.1073/pnas.1621363114

cGAS is essential for the antitumor effect of immune checkpoint blockade

Proc Natl Acad Sci U S A. 2017 Feb 14;114(7):1637-1642. doi: 10.1073/pnas.1621363114. Epub 2017 Jan 30.

Authors

Hua Wang¹, Shuiqing Hu¹, Xiang Chen^{1

2}, Heping Shi^{1

3}, Chuo Chen³, Lijun Sun^{1

2}, Zhijian J Chen^{4

2}

Affiliations

¹ Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148.
² Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148.
³ Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148.
⁴ Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148; [email protected].

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.

Keywords: PD-L1; STING; cGAMP; cGAS; cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies / administration & dosage
Antibodies / immunology
Antibodies / pharmacology
Antineoplastic Combined Chemotherapy Protocols / pharmacology
B7-H1 Antigen / antagonists & inhibitors
B7-H1 Antigen / immunology
B7-H1 Antigen / metabolism
Cell Line, Tumor
Cells, Cultured
Cross-Priming / drug effects
Cross-Priming / immunology
Dendritic Cells / drug effects
Dendritic Cells / immunology
Dendritic Cells / metabolism
Immunity, Innate / drug effects
Immunity, Innate / immunology*
Melanoma, Experimental / drug therapy
Melanoma, Experimental / immunology*
Melanoma, Experimental / metabolism
Mice, Inbred C57BL
Mice, Knockout
Nucleotides, Cyclic / administration & dosage
Nucleotides, Cyclic / immunology*
Nucleotides, Cyclic / pharmacology
Nucleotidyltransferases / genetics
Nucleotidyltransferases / immunology*
Nucleotidyltransferases / metabolism
Survival Analysis

Substances

Antibodies
B7-H1 Antigen
Cd274 protein, mouse
Nucleotides, Cyclic
cyclic guanosine monophosphate-adenosine monophosphate
Nucleotidyltransferases
cGAS protein, mouse