STING signaling remodels the tumor microenvironment by antagonizing myeloid-derived suppressor cell expansion
STING signaling remodels the tumor microenvironment by antagonizing myeloid-derived suppressor cell expansion
复制标题
STING 信号传导通过拮抗骨髓源性抑制细胞扩张来重塑肿瘤微环境
DOI：
10.1038/s41418-019-0302-0
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发表时间：
2019
影响因子：
12.4
通讯作者：
Cui Jun
中科院分区：
文献类型：
--
作者：
Zhang Chuanxia;Ye Shubiao;Ni Jianjiao;Cai Tingting;Liu Yina;Huang Daijia;Mai Haiqiang;Chen Qiuyan;He Jia;Zhang Xiaoshi;Zeng Yixin;Li Jiang;Cui Jun
干扰素基因刺激物(STING)是抗病毒天然免疫信号的主要适配蛋白，被认为是抗病毒和抗肿瘤免疫最重要的调节因子之一。尽管STING激动剂作为一类促进肿瘤免疫治疗的新型佐剂在临床试验中得到了广泛的研究，但STING通路在塑造肿瘤微环境中的内在作用仍存在争议。在此，我们发现在EB病毒相关性鼻咽癌(NPC)中，STING在调节髓系来源的抑制细胞(MDSC)分化和抗肿瘤免疫中起着至关重要的作用。机制分析显示，STING通过增强肿瘤细胞和MDSC中SOCS1的表达来抑制鼻咽癌来源的MDSC的诱导。SOCS1通过其SH2结构域与STAT3物理相互作用，阻止STAT3的磷酸化和二聚化，从而通过抑制GM-CSF和IL-6的产生而减少对MDSC的诱导。值得注意的是，肿瘤刺痛表达的减少被发现与鼻咽癌患者的不良预后显著相关。我们的发现揭示了一种新的机制，将刺痛与肿瘤微环境细胞因子的产生和MDSC的诱导联系起来。
Stimulator of interferon genes (STING), a major adaptor protein in antiviral innate immune signaling, is considered as one of the most important regulators of antiviral and antitumor immunity. Although STING agonists are now intensively studied in clinical trials as a new class of adjuvants to boost cancer immunotherapy, the tumor-intrinsic role of the STING pathway in shaping the tumor microenvironment remains controversial. Here, we discovered that STING plays a vital role in regulation of myeloid-derived suppressor cell (MDSC) differentiation and antitumor immunity in Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC). Mechanistic analyses reveal that STING represses NPC-derived MDSC induction by enhancing SOCS1 expression in both tumor cells and MDSCs. SOCS1 physically interacts with STAT3 through its SH2 domain to prevent STAT3 phosphorylation and dimerization, resulting in reduced MDSC induction via inhibition of GM-CSF and IL-6 production. Notably, reduced tumoral STING expression was found to be significantly associated with a poor prognosis for NPC patients. Our findings reveal a novel mechanism linking STING to tumor microenvironmental cytokine production and MDSC induction.