LMP1/Lgals1蛋白复合体调控转录因子IRF-1促进鼻咽癌细胞免疫逃逸

Recurrence and metastasis of nasopharyngeal carcinoma is closely related to immune escape. It is known that LMP1 can promote the immune escape of nasopharyngeal carcinoma cells by controlling expression of PD-L1 while the mechanism has not yet been fully clarified. However, specific key protein may serve as a therapeutic target. .Our preliminary study found that Lgals1 protein ligates LMP1 and TRAF6 protein, which can not only up-regulates the transcription level of IRF-1 but also promotes the phosphorylation of IRF-1 and enhances its transcriptional activity. .In this study , on one hand, we will confirm the binding site of LMP1, TRAF6 and Lgals1, and we will explain the way how LMP1/Lgals1/TRAF6 regulate the transcription and the post translational modification of IRF-1, which enhances the expression of PD-L1; on the other hand, Lgals1's role in promoting tumor invasion, metastasis and immune escape will be tested at the cell and animal level in order to preliminarily verify the treatment effect of the therapeutic method that regards Lgals1 as the target. The relationship between Lgals1 protein level and metastasis will be explored by clinical pathology, molecular image techniques and liquid biopsy..We are trying to make it clear that Lgals1 protein, as a therapeutic target, can apply in the estimation of curative effect and the screening for high-risk recurrent and metastasizing patients to lay solid foundations for translational medicine research.

鼻咽癌复发及转移与免疫逃逸密切相关，已知LMP1调控PD-L1表达促进鼻咽癌免疫逃逸，但机制尚未完全阐明，其中特异性关键蛋白或可作为治疗靶点。我们前期实验发现Lgals1蛋白联结LMP1蛋白与TRAF6蛋白，不仅上调IRF-1转录水平，而且促进IRF-1蛋白磷酸化修饰，增强IRF-1转录活性。本课题将在分子层面鉴定LMP1、TRAF6与Lgals1的结合位点，阐明LMP1/Lgals1/TRAF6调控IRF-1基因转录与蛋白翻译后修饰，进而增强PD-L1表达的机制；并在细胞与动物水平证明Lgals1促进肿瘤侵袭转移与免疫逃逸功能，初步验证Lgals1作为靶点的治疗效果；并结合临床病理、分子影像和液态活检，探索Lgals1蛋白与患者复发转移的关系。本课题将明确Lgals1蛋白应用于评价疗效与筛选复发、转移高危病人的可能性，以及作为治疗靶点的可行性，为后续转化医学研究奠定基础。

复发或转移鼻咽癌患者的5年生存率低于10%，免疫治疗的出现为这部分患者带来治疗曙光，然而仅20%-30%患者能从中获益。探索鼻咽癌EB病毒编码蛋白与肿瘤免疫逃逸的相关性，能够更好的理解肿瘤微环境，将有助于选择合适的患者和药物以提高临床治疗效果。本项目寻找到LMP1的互作蛋白Lgals1，证明LMP1/Lgals1可通过IRF-1调控 PD-L1的表达，抑制CD8+T细胞杀伤功能及活化能力，进而影响鼻咽癌的免疫逃逸；在对鼻咽癌临床样本进行分析时还发现，PD-L1的表达也是鼻咽癌免疫治疗有效的预后标志物；同时，我们还发现另一EBV编码的潜伏LMP-2A也可通过调控免疫检查点CD200和CD155来影响鼻咽癌细胞的免疫逃逸或是侵袭与迁移。本研究成果不仅将为鼻咽癌免疫治疗提供新的治疗靶点，同时也为鼻咽癌免疫治疗效果的评估提供新的方法，推动鼻咽癌免疫治疗的进展。