靶向EZH2可减少LMP1诱导的活化调节性T细胞，增强鼻咽癌的抗肿瘤免疫力。

Targeting EZH2 depletes LMP1-induced activated regulatory T cells enhancing antitumor immunity in nasopharyngeal carcinoma.

作者信息

Sun Wei, Chen Lin, Tang Jun, Zhang Chengcheng, Wen Yihui, Wen Weiping

机构信息

Department of Otorhinolaryngology-Head and Neck Surgery; Guangzhou Key Laboratory of Otorhinolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

Department of Otorhinolaryngology Head and Neck Surgery, The First People's Hospital of Foshan, Foshan, China.

出版信息

J Cancer Res Ther. 2020;16(2):309-319. doi: 10.4103/jcrt.JCRT_986_19.

DOI:10.4103/jcrt.JCRT_986_19

PMID:32474518

Abstract

OBJECTIVE

Regulatory T cells (Tregs) are critical factors that impair antitumor immunity. Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) is one of the most pathogenic factors in nasopharyngeal carcinoma (NPC). However, the role of EBV-encoded LMP1 in regulating Treg generation in NPC remains unclear.

MATERIALS AND METHODS

The in vitro stability of activated Tregs (aTregs) influenced by LMP1 was analyzed by flow cytometry. The inhibitory effects of LMP1-HONE1 antigen-induced aTregs on tumor-associated antigen (TAA)-specific T cells were analyzed in vitro and in vivo. Finally, the expression of LMP1, Foxp3, and enhancer of zeste homolog 2 (EZH2) were analyzed in samples from 86 NPC patients by immunohistochemistry and immunofluorescence.

RESULTS

LMP1 upregulated the expression of EZH2, which increased the stability of aTregs in vitro. EZH2 inhibitor, DZnep, depleted LMP1-HONE1 antigen-induced aTregs in vitro and led to potent TAA-specific T cell antitumor immunity in vivo. In NPC tissues, LMP1 expression level was positively correlated with the number of EZH2 Tregs, which was positively correlated with clinical stage and overall survival.

CONCLUSIONS

EZH2 is essential for maintaining the stability and inhibitory functions of aTregs that are induced by EBV-encoded LMP1 in NPC.

摘要

目的

调节性T细胞（Tregs）是损害抗肿瘤免疫的关键因素。爱泼斯坦-巴尔病毒（EBV）编码的潜伏膜蛋白1（LMP1）是鼻咽癌（NPC）中最具致病力的因素之一。然而，EBV编码的LMP1在NPC中调节Treg生成的作用仍不清楚。

材料与方法

通过流式细胞术分析受LMP1影响的活化Tregs（aTregs）的体外稳定性。在体外和体内分析LMP1-HONE1抗原诱导的aTregs对肿瘤相关抗原（TAA）特异性T细胞的抑制作用。最后，通过免疫组织化学和免疫荧光分析86例NPC患者样本中LMP1、叉头框蛋白3（Foxp3）和zeste同源物2增强子（EZH2）的表达。

结果

LMP1上调EZH2的表达，这增加了aTregs在体外的稳定性。EZH2抑制剂DZnep在体外消耗LMP1-HONE1抗原诱导的aTregs，并在体内导致有效的TAA特异性T细胞抗肿瘤免疫。在NPC组织中，LMP1表达水平与EZH2阳性Tregs数量呈正相关，而EZH2阳性Tregs数量与临床分期和总生存期呈正相关。