外泌体长链非编码RNA lncUEET促进肝癌CD8+T细胞耗竭的机制研究及临床应用探索

在肿瘤微环境中，抗肿瘤免疫的主要效应细胞CD8+T细胞的功能常受抑制，称为T细胞耗竭。本课题组前期研究发现，外泌体长链非编码RNA lncUEET与肝癌T细胞耗竭程度显著相关，且外泌体可介导lncUETE在耗竭性和非耗竭性CD8+T细胞间传递，并抑制后者的功能。据此我们提出：外泌体lncUEET可否作为延缓或逆转CD8+T细胞耗竭的干预靶点？可否作为预测肝癌患者预后及免疫治疗疗效的标志物？为此，本课题将利用转录组测序和蛋白免疫共沉淀等，探究外泌体lncUEET在CD8+T细胞间传递的机制及lncUEET调控CD8+T细胞功能的分子机制；并在体外、3D培养体系以及免疫缺陷鼠肝癌模型中探索通过干预lncUEET表达来逆转CD8+T耗竭并增强其抗肿瘤效应的潜在价值(体内、体外功能验证)；在此基础上，我们拟进行临床随访研究外泌体lncUEET作为新型标志物，预测肝癌患者预后及免疫治疗疗效的可能性。

In tumor microenvironment, CD8+T cells, as the primary anti-tumor effector cells, are usually in dysfunctional states called T cell exhaustion. Our previous study revealed that the expression levels of exosomal lncRNA UEET are significantly correlated with the percentages of exhuasted T cells in hepatocellular carcinoma (HCC). Moreover, exosomes can transfer lcnUEET from exhuasted T cells to non-exhausted ones and impared the anti-tumor functionalities of the latter. Thus, we propose: whether exosomal lcnUEET can serve as a potential therapeutic target to deter or reverse T cell exhuastion? Or as a biomarker for T cell exhaustion and immunotherapy efficacies? Therefore, we will investigate the mechanisms of lcnUEET transferring by exosomes among T cells, and the effects as well as the underlying mechanims of lncUEET on CD8+T cell functions through gain- and loss-of-function experiments in vitro and in vivo. At last, we will explore the possibility of exosomal lncUEET as a biomarker for HCC patients receiving or not receiving immunotherapies.