EBV潜伏膜蛋白LMP1介导MHC-I/II抑制和PD-L1上调在鼻咽癌免疫逃逸中的作用及联合免疫治疗策略探索

大量淋巴细胞浸润及PD-L1高表达提示鼻咽癌是“热肿瘤”，适合免疫治疗，但抗PD-(L)1治疗在鼻咽癌中的有效率并不高，具体原因不清楚。我们前期阐明了EBV潜伏膜蛋白LMP1在鼻咽癌中通过活化下游癌基因信号上调PD-L1，且与IFN-γ有协同效应。我们新发现EBV可通过LMP1抑制MHC-I/II，且与IFN-γ有拮抗效应。我们将围绕以下几个方面深入研究：探讨LMP1对MHC-I/II、PD-L1的主动调控与IFN-γ介导的适应性调控之间的机制差异及其相互作用；探索联合诱导MHC-I/II上调与抗PD-(L)1来提高免疫治疗疗效的可行性；临床标本分析MHC-1/II、PD-L1、浸润淋巴细胞、肿瘤突变与患者预后及抗PD-(L)1疗效的关系。本研究将揭示鼻咽癌免疫逃逸新机制并探索诱导MHC-I/II上调与抗PD-(L)1联合治疗的新策略，为鼻咽癌及其它EBV阳性肿瘤免疫治疗优化提供新的思路。

Large number of lymphocyte infiltration and high expression of PD-L1 suggest that nasopharyngeal carcinoma is a "hot tumor" and is suitable for immunotherapy. However, the efficacy of anti-PD-(L)1 monotherapy in nasopharyngeal carcinoma is not high, and the exact reason is still unknown. In our previous experiments, we elucidated that EBV latent membrane protein LMP1 could up-regulate PD-L1 by activating downstream oncogene signals in nasopharyngeal carcinoma, which had a synergistic effect with IFN-γ. We newly discovered that EBV could inhibit MHC-I/II by LMP1 and had an antagonistic effect with IFN-γ. We will conduct in-depth research around the following aspects in this project: exploring the difference and interaction of their mechanism between active regulation and adaptive regulation of LMP1 and IFN-γon MHC-I/II and PD-L1; exploring the feasibility of combining induction of MHC-I/II up-regulation and anti-PD-(L)1 drug therapy in improving immunotherapy efficacy; using clinical specimens to analysis the association between MHC-1/II, PD-L1, infiltrating lymphocytes, tumor mutation and prognosis of patients and anti-PD-(L)1 efficacy. This study will reveal the new immune escape mechanism of nasopharyngeal carcinoma and explore new combining immunotherapy strategies, which will combine MHC-I/II up-regulation and anti-PD-(L)1 treatment. This project will provide new ideas to optimize immunotherapy in nasopharyngeal carcinoma and other EBV-positive tumors.