Antitumor Activity of cGAMP via Stimulation of cGAS-cGAMP-STING-IRF3 Mediated Innate Immune Response

Abstract

Immunotherapy is one of the key strategies for cancer treatment. The cGAS-cGAMP-STING-IRF3 pathway of cytosolic DNA sensing plays a pivotal role in antiviral defense. We report that the STING activator cGAMP possesses significant antitumor activity in mice by triggering the STING-dependent pathway directly. cGAMP enhances innate immune responses by inducing production of cytokines such as interferon-β, interferon-γ, and stimulating dendritic cells activation, which induces the cross-priming of CD8+ T cells. The antitumor mechanism of cGAMP was verified by STING and IRF3, which were up-regulated upon cGAMP treatment. STING-deficiency dramatically reduced the antitumor effect of cGAMP. Furthermore, cGAMP improved the antitumor activity of 5-FU, and clearly reduced the toxicity of 5-FU. These results demonstrated that cGAMP is a novel antitumor agent and has potential applications in cancer immunotherapy.

cGAS-mediated control of blood-stage malaria promotes Plasmodium-specific germinal center responses

“…While differences in type I IFN production at the protein level were present late during infection, cGAS may drive production of other cytokines. For example, increased serum levels of IL-12, TNF, and CCL2 have been reported in mice treated with exogenous cGAMP (the secondary messenger produced by cGAS) (65,66).…”

“…To examine antigen-specific CD4 + T cells responding to infection, P. yoelii were generated that constitutively express the Lymphocytic choriomeningitis virus-derived (LCMV-derived) glycoprotein (GP) epitope (GP [61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80] ). This allows for the identification and analysis of antigen-specific CD4 + T cells using previously described GP66:I-A B tetramer enrichment strategies (16).…”

The host STING pathway at the interface of cancer and immunity

“…An enhancement of antitumor efficacy using STING agonists combined with a chemotherapeutic agent was reported using daily i.v. injections of mammalian cGAMP and 5-fluorouracil in the mouse CT26 colon carcinoma model (88). Combined radiotherapy and intratumorally administered CDN also worked synergistically to induce antitumor immune responses in the MC38 colon carcinoma model and PancO2 pancreatic cancer model via a mechanism involving enhancement of tumorspecific CD8 + T cell immunity (73,83).…”

An RNA-Based Fluorescent Biosensor for High-Throughput Analysis of the cGAS-cGAMP-STING Pathway

“…Based on our positive results in detecting cGAS overexpression in bacteria (Fig S3), we considered applying the fluorescent biosensor to detect cellular cGAMP levels in mammalian cell lysates. 2′, 3′-cGAMP is produced by cGAS+ mammalian cells as part of a cytosolic immune surveillance pathway for foreign DNA, which could be caused by viral or bacterial infection, and alternatively, by leakage of damaged nuclear or mitochondrial DNA (Gao et al, 2013a; Hansen et al, 2014; Li et al, 2016; Ma and Damania, 2016; Watson et al, 2015; White et al, 2014; Woo et al, 2015a). A standard method to simulate these conditions is to transfect cells with double-stranded DNA, however it has not been straightforward to directly measure the levels of 2′, 3′-cGAMP produced.…”