T细胞功能耗竭是恶性肿瘤免疫逃逸和免疫治疗失败的主要原因，先天性免疫细胞失衡与慢性病毒感染是T细胞功能耗竭的主要诱因，但鼻咽癌微环境调控T细胞功能耗竭的分子机制至今尚不明确。我们前期发现鼻咽癌微环境肿瘤exosome（T-EXO）及其携带miRNA参与了T细胞功能失活的调控、髓源性抑制细胞（MDSC）数目的扩增，且与STING蛋白表达及其信号通路活性下调相关联。在本项目中，我们通过RNA表达芯片或测序技术、生物信息分析、基因编辑技术、免疫实验等方法筛查T-EXO富集的miRNA/lncRNA，探讨T-EXO富集miRNA/lncRNA靶向STING分子和信号通路的调控机制，及影响MDSC分化和参与T细胞功能耗竭的作用；最后通过动物实验探讨靶向非编码RNA或STING通路相关基因的小分子药物在鼻咽癌免疫治疗中的作用。我们预期发现鼻咽癌T细胞功能耗竭的调控机制、预后评估标志及潜在的免疫治疗靶点

The T-cell exhaustion is the main cause of tumor escape and the failure of tumor immunotherapy, and the imbalance of innate immunity and choric virus infection is linked to T-cell exhaustion in malignancies, however the main molecular mechanism of underway T-cell exhaustion in tumor microenvironments of nasopharyngeal carcinoma (NPC) is still largely unknown. We showed that the T-EXO and its carried miRNAs mediated the T-cell function impaired, Myeloid-derived suppressor cell (MDSC) expansion and the activity of STING signaling pathway which regulate the innate immune responses and was down-regulated in NPC in our previous study. Here, we supposed that T-EXO-carried non-coding RNAs regulate the T-cell exhaustion via down-regulating the STING signaling pathway in NPC. Firstly, we screen the different expression profile of T-EXO-carried miRNA/lncRNA in NPC by the microarray of non-coding RNA expression chip or RNA-sequencing array, then we analyze the regulations between the T-EXO-carried miRNAs/lncRNAs and their target genes in STING signaling pathway, and their effect on the MDSC differentiation and T-cell function through gene overexpression or knockout, FACS staining, immunoblotting or RNAchip et al. In addition, we will explore the immunotherapy strategy for NPC by small molecular drug targeting the potential target miRNA/lncRNA or target genes in STING signaling pathway by in vitro and in vivo analysis (xenograft mouse model). We expect to find out the biomarkers of prognosis or the potential targets for immunotherapy in NPC, and help to improve the clinical benefit of TIL immunotherapy of NPC patients.