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

Research output: Contribution to journalArticle

77 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1637-1642
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number7
DOIs
StatePublished - Feb 14 2017

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Adenosine Monophosphate
Cross-Priming
Interferon Type I
Experimental Melanomas
Antibodies
Second Messenger Systems
Neoplasm Antigens
Growth
Innate Immunity
Immunotherapy
Dendritic Cells
cyclic guanosine monophosphate-adenosine monophosphate
Immunity
Melanoma
Neoplasms
Therapeutics
T-Lymphocytes
DNA
Proteins

Keywords

  • Cancer
  • cGAMP
  • cGAS
  • PD-L1
  • STING

ASJC Scopus subject areas

  • General

Cite this

cGAS is essential for the antitumor effect of immune checkpoint blockade. / Wang, Hua; Hu, Shuiqing; Chen, Xiang; Shi, Heping; Chen, Chuo; Sun, Lijun; Chen, Zhijian J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 7, 14.02.2017, p. 1637-1642.

Research output: Contribution to journalArticle

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AU - Shi, Heping

AU - Chen, Chuo

AU - Sun, Lijun

AU - Chen, Zhijian J.

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