Fang Wenfeng, Zhang Jianwei, Hong Shaodong, Zhan Jianhua, Chen Nan, Qin Tao, Tang Yanna, Zhang Yaxiong, Kang Shiyang, Zhou Ting, Wu Xuan, Liang Wenhua, Hu Zhihuang, Ma Yuxiang, Zhao Yuanyuan, Tian Ying, Yang Yunpeng, Xue Cong, Yan Yue, Hou Xue, Huang Peiyu, Huang Yan, Zhao Hongyun, Zhang Li
State Key laboratory of Oncology in South China, Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, P. R. China. Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
Department of Oncology, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Oncotarget. 2014 Dec 15;5(23):12189-202. doi: 10.18632/oncotarget.2608.
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-γ 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 induced PD-L1. 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-κB pathways. Besides, IFN-γ 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.
程序性死亡受体配体1（PD-L1）表达是爱泼斯坦-巴尔病毒（EBV）相关恶性肿瘤（如鼻咽癌（NPC））的一个特征。在此，我们发现EBV诱导的潜伏膜蛋白1（LMP1）和γ干扰素（IFN-γ）信号通路协同调节程序性细胞死亡蛋白1配体（PD-L1）。与EBV阴性细胞系相比，EBV阳性NPC细胞系中PD-L1的表达更高。外源性和内源性诱导LMP1均可增加PD-L1的表达。同样，在EBV阳性细胞系中敲低LMP1可抑制PD-L1的表达。我们进一步证明，LMP1通过信号转导和转录激活因子3（STAT3）、激活蛋白1（AP-1）和核因子κB（NF-κB）信号通路上调PD-L1。此外，在NPC中，IFN-γ独立于LMP1但与之协同上调PD-L1。此外，我们还表明，PD-L1与NPC患者较差的无病生存率相关。这些结果表明，阻断LMP1致癌信号通路和PD-1/PD-L1免疫检查点可能是EBV阳性NPC患者一种有前景的治疗方法。
Zotero 插件
