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

// Wenfeng Fang 1,2,* , Jianwei Zhang 3,* , Shaodong Hong 1,2,* , Jianhua Zhan 1,2,* , Nan Chen 4 , Tao Qin 1,2 , Yanna Tang 4 , Yaxiong Zhang 1,2 , Shiyang Kang 1,2 , Ting Zhou 1,2 , Xuan Wu 1,2 , Wenhua Liang 1,2 , Zhihuang Hu 1,2 , Yuxiang Ma 1,2 , Yuanyuan Zhao 1,2 , Ying Tian 1,2 , Yunpeng Yang 1,2 , Cong Xue 1,2 , Yue Yan 1,2 , Xue Hou 1,2 , Peiyu Huang 1,2 , Yan Huang 1,2 , Hongyun Zhao 1,2 and Li Zhang 1,2 1 State Key laboratory of Oncology in South China, Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, P. R. China 2 Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China 3 Department of Oncology, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China 4 Department of Oncology, the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China * These authors contributed equally to this work Correspondence: Li Zhang, email: // Keywords : Nasopharyngeal carcinoma (NPC); latent membrane protein 1 (LMP1); PD-L1; Epstein–Barr virus (EBV) Received : July 20, 2014 Accepted : October 21, 2014 Published : October 21, 2014 Abstract 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.