cGAS is essential for the antitumor effect of immune checkpoint blockade

H Wang, S Hu, X Chen, H Shi… - Proceedings of the …, 2017 - National Acad Sciences
H Wang, S Hu, X Chen, H Shi, C Chen, L Sun, ZJ Chen
Proceedings of the National Academy of Sciences, 2017National Acad Sciences
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 …
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.
National Acad Sciences