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

Tiejun Li,Chang Shu,Xiangshi Tan,Qiming Xu,Jason Tan,Pingwei Li,Hong Yuan,Yaocheng Rui,Pengbiao Xu,Hao Cheng,Yuefan Zhang

doi:10.1038/srep19049

Tiejun Li, Chang Shu + Show 9 more

Open Access

https://doi.org/10.1038/srep19049

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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.

Highlights

(STING) locating in the ER membrane14. cGAMP induces a conformational change of STING, leading to the recruitment and activation of protein kinase TBK1 at the signaling complex
The transfer of cGAMP by viruses may represent a defense mechanism to propagate immune responses to uninfected target cells29. cGAMP is a critical stimulator of cGAS-cGAMP-STING-interferon regulatory factor 3 (IRF3)-mediated innate immune responses and is a high affinity endogenous activator of STING, we reasoned that cGAMP should promote antitumor immune responses in addition to its antiviral activity
It has been demonstrated that cGAMP is an endogenous activator of STING and it is generated in mammalian cells by cGAS in response to double-strand DNA in the cytoplasm[13,19,30]

Summary

Introduction

(STING) locating in the ER membrane14. cGAMP induces a conformational change of STING, leading to the recruitment and activation of protein kinase TBK1 at the signaling complex. CGAMP induces a conformational change of STING, leading to the recruitment and activation of protein kinase TBK1 at the signaling complex. Recent studies showed that STING-dependent cytosolic DNA sensing can mediate innate immune recognition of immunogenic tumors, and promote type-I IFN dependent antitumor immunity after radiation therapy[18,19]. A novel cGAS-cGAMP-STING-IRF3 pathway of cytosolic sensing and signaling has been verified to mediate innate immune response, and plays pivotal roles in antiviral defense[27]. CGAMP is a critical stimulator of cGAS-cGAMP-STING-IRF3-mediated innate immune responses and is a high affinity endogenous activator of STING, we reasoned that cGAMP should promote antitumor immune responses in addition to its antiviral activity. Our results established a solid basis for the development of cGAMP as a potential new antitumor immunotherapy drug

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