Antitumor Activity of cGAMP via Stimulation of cGAS-cGAMP-STING-IRF3 Mediated Innate Immune Response.
Antitumor Activity of cGAMP via Stimulation of cGAS-cGAMP-STING-IRF3 Mediated Innate Immune Response.
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cGAMP 通过刺激 cGAS-cGAMPSTING-IRF3 介导的先天免疫反应发挥抗肿瘤活性
DOI：
10.1038/srep19049
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发表时间：
2016-01-12
影响因子：
4.6
通讯作者：
Tan X
中科院分区：
文献类型：
--
作者：
Li T;Cheng H;Yuan H;Xu Q;Shu C;Zhang Y;Xu P;Tan J;Rui Y;Li P;Tan X
免疫治疗是癌症治疗的关键策略之一。胞质DNA传感的cGAS-cGAMP-STING-IRF 3途径在抗病毒防御中起关键作用。我们报道STING激活剂cGAMP通过直接触发STING依赖性途径在小鼠中具有显著的抗肿瘤活性。cGAMP通过诱导细胞因子如干扰素-β、干扰素-γ的产生和刺激树突状细胞活化（其诱导CD 8 + T细胞的交叉致敏）来增强先天性免疫应答。cGAMP的抗肿瘤机制通过STING和IRF 3验证，STING和IRF 3在cGAMP处理后上调。STING缺陷显著降低了cGAMP的抗肿瘤作用。cGAMP能提高5-FU的抗肿瘤活性，明显降低5-FU的毒性。这些结果表明cGAMP是一种新型抗肿瘤药物，在肿瘤免疫治疗中具有潜在的应用前景。
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.