EBV潜伏膜蛋白LMP1通过CD47促进NK/T细胞淋巴瘤T细胞耗竭的机制研究

NK/T细胞淋巴瘤（NKTCL）是一种与EBV感染密切相关的侵袭性淋巴瘤，其复发难治患者预后极差，亟需新的治疗策略。我们的前期工作发现NKTCL患者存在显著的T细胞耗竭，表现为T细胞表面抑制性受体高表达、细胞增殖及效应细胞因子产生受抑，而EBV癌蛋白LMP1及CD47可导致T细胞耗竭，且CD47基因启动子区域存在LMP1下游NF-κB的结合位点。因此我们推测LMP1可通过激活NF-κB通路促进CD47转录，CD47高表达后造成NKTCL的T细胞耗竭。为验证该假说，本课题拟上调及下调NKTCL的LMP1表达，确认LMP1对T细胞耗竭的作用及对CD47的促转录作用；并通过下调或靶向抑制CD47，明确CD47介导LMP1对T细胞耗竭的促进作用；最后采用患者组织标本验证LMP1及CD47与T细胞耗竭的关系。本研究有助于阐明NKTCL患者T细胞耗竭的机制，并有望为其肿瘤免疫治疗提供新的治疗靶点。

NK/T cell lymphoma (NKTCL) is an aggressive lymphoma associated with chronic persistent EBV infection, despite of the fact that great improvement has been achieved in recent decades, novel treatment strategies is still urgently needed, especially for relapse and refractory individuals. Our previous work showed that NKTCL patients are characterized by obvious T cell exhaustion, evidenced by upregulated multiple inhibitory receptors, decreased cell proliferation and cytokine secretion. Further study revealed that LMP1, an important oncoprotein encoded by EBV, as well as CD47, is capable of inducing T cell exhaustion. We hypothesis that LMP1 upregulates CD47 expression by promoting its transcription via activation of NF-κB, which binds to the promoter of CD47, resulting in T cell exhaustion. To elucidate this, firstly we plan to upregulate or downregulate LMP1 in NKTCL cell lines to confirm its effect on T cell exhaustion, meanwhile CHIP and co-luciferase assay will be carried out to verify impact of LMP1 on transcription of CD47. Followingly, reversal of effect of LMP1 on T cell exhaustion will be verified by downregulating or inhibiting CD47. Lastly, tumor tissues of NKTCL patients will be collected to further correlate LMP1 and CD47 and T cell exhaustion. Our study will elucidate the mechanism of T cell exhaustion in NKTCL, also make it possible to find a new target for immunotherapy for NKTCL patients.