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.

• Authors: Tiejun Li, Hao Cheng, Hong Yuan, Qiming Xu, Chang Shu, Yuefan Zhang, Pengbiao Xu, Jason Tan, Yaocheng Rui, Pingwei Li, Xiangshi Tan
• Journal: Scientific reports (Sci Rep) Vol. 6 Pg. 19049 (Jan 12 2016) ISSN: 2045-2322 [Electronic] England
• PMID: 26754564 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cytokines
• Interferon Regulatory Factor-3
• Irf3 protein, mouse
• Membrane Proteins
• Nucleotides, Cyclic
• Sting1 protein, mouse
• cyclic guanosine monophosphate-adenosine monophosphate
• Nucleotidyltransferases
• cGAS protein, mouse
• Fluorouracil

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cytokines (metabolism)
• Dendritic Cells (drug effects, metabolism)
• Fluorouracil (pharmacology, toxicity)
• Immunity, Innate (drug effects)
• Interferon Regulatory Factor-3 (metabolism)
• Membrane Proteins (metabolism)
• Mice, Inbred BALB C
• Nucleotides, Cyclic (pharmacology)
• Nucleotidyltransferases (metabolism)