EBV-driven LMP1 and IFN-γ up-regulate PD-L1 in nasopharyngeal carcinoma: Implications for oncotargeted therapy

被引:341
作者
Fang, Wenfeng [1 ,2 ]
Zhang, Jianwei [3 ]
Hong, Shaodong [1 ,2 ]
Zhan, Jianhua [1 ,2 ]
Chen, Nan [4 ]
Qin, Tao [1 ,2 ]
Tang, Yanna [4 ]
Zhang, Yaxiong [1 ,2 ]
Kang, Shiyang [1 ,2 ]
Zhou, Ting [1 ,2 ]
Wu, Xuan [1 ,2 ]
Liang, Wenhua [1 ,2 ]
Hu, Zhihuang [1 ,2 ]
Ma, Yuxiang [1 ,2 ]
Zhao, Yuanyuan [1 ,2 ]
Tian, Ying [1 ,2 ]
Yang, Yunpeng [1 ,2 ]
Xue, Cong [1 ,2 ]
Yan, Yue [1 ,2 ]
Hou, Xue [1 ,2 ]
Huang, Peiyu [1 ,2 ]
Huang, Yan [1 ,2 ]
Zhao, Hongyun [1 ,2 ]
Zhang, Li [1 ,2 ]
机构
[1] Sun Yat Sen Univ, Ctr Canc, Dept Med Oncol, State Key Lab Oncol South China, Guangzhou 510275, Guangdong, Peoples R China
[2] Sun Yat Sen Univ, Ctr Canc, Collaborat Innovat Ctr Canc Med, Guangzhou 510275, Guangdong, Peoples R China
[3] Sun Yat Sen Univ, Affiliated Hosp 6, Dept Oncol, Guangzhou 510275, Guangdong, Peoples R China
[4] Sun Yat Sen Univ, Affiliated Hosp 5, Dept Oncol, Zhuhai, Guangdong, Peoples R China
基金
国家高技术研究发展计划(863计划);
关键词
Nasopharyngeal carcinoma (NPC); latent membrane protein 1 (LMP1); PD-L1; Epstein-Barr virus (EBV); EPSTEIN-BARR-VIRUS; LATENT MEMBRANE PROTEIN-1; HPV-ASSOCIATED HEAD; B7-H1; EXPRESSION; T-LYMPHOCYTES; CANCER; PATHWAY; CELLS; PATHOGENESIS; INFECTION;
D O I
10.18632/oncotarget.2608
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
PD-L1 expression is a feature of Epstein-Barr virus (EBV) associated malignancies such as nasopharyngeal carcinoma (NPC). Here, we found that EBV-induced latent membrane protein 1 (LMP1) and IFN-gamma pathways cooperate to regulate programmed cell death protein 1 ligand (PD-L1). Expression of PD-L1 was higher in EBV positive NPC cell lines compared with EBV negative cell lines. PD-L1 expression could be increased by exogenous and endogenous induction of LMP1. In agreement, expression of PD-L1 was suppressed by knocking down LMP1 in EBV positive cell lines. We further demonstrated that LMP1 up-regulated PD-L1 through STAT3, AP-1, and NF-kappa B pathways. Besides, IFN-gamma was independent of but synergetic with LMP1 in up-regulating PD-L1 in NPC. Furthermore, we showed that PD-L1 was associated with worse disease-free survival in NPC patients. These results imply that blocking both the LMP1 oncogenic pathway and PD-1/PD-L1 checkpoints may be a promising therapeutic approach for EBV positive NPC patients.
引用
收藏
页码:12189 / 12202
页数:14
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