EBV-driven LMP1 and IFN-γ up-regulate PD-L1 in nasopharyngeal carcinoma: Implications for oncotargeted therapy
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Wenfeng Fang1,2,*, Jianwei Zhang3,*, Shaodong Hong1,2,*, Jianhua Zhan1,2,*, Nan Chen4, Tao Qin1,2, Yanna Tang4, Yaxiong Zhang1,2, Shiyang Kang1,2, Ting Zhou1,2, Xuan Wu1,2, Wenhua Liang1,2, Zhihuang Hu1,2, Yuxiang Ma1,2, Yuanyuan Zhao1,2, Ying Tian1,2, Yunpeng Yang1,2, Cong Xue1,2, Yue Yan1,2, Xue Hou1,2, Peiyu Huang1,2, Yan Huang1,2, Hongyun Zhao1,2 and Li Zhang1,2
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
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
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.
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