通过刺激cGAS-cGAMP-STING-IRF3介导的固有免疫反应研究cGAMP的抗肿瘤活性
Antitumor Activity of cGAMP via Stimulation of cGAS-cGAMP-STING-IRF3 Mediated Innate Immune Response.
作者信息
Li Tiejun, Cheng Hao, Yuan Hong, Xu Qiming, Shu Chang, Zhang Yuefan, Xu Pengbiao, Tan Jason, Rui Yaocheng, Li Pingwei, Tan Xiangshi
机构信息
Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China.
Department of Chemistry &Shanghai Key Laboratory of Chemical Biology for Protein Research and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200433, China.
出版信息
Sci Rep. 2016 Jan 12;6:19049. doi: 10.1038/srep19049.
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.
免疫疗法是癌症治疗的关键策略之一。胞质DNA感应的cGAS-cGAMP-STING-IRF3途径在抗病毒防御中起关键作用。我们报告称，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的产生以及刺激树突状细胞活化来增强先天免疫反应，从而诱导CD8(+) T细胞的交叉启动。cGAMP的抗肿瘤机制通过STING和IRF3得到验证，它们在cGAMP处理后上调。STING缺陷显著降低了cGAMP的抗肿瘤作用。此外，cGAMP提高了5-氟尿嘧啶的抗肿瘤活性，并明显降低了5-氟尿嘧啶的毒性。这些结果表明，cGAMP是一种新型抗肿瘤药物，在癌症免疫治疗中具有潜在应用价值。
Zotero 插件