title: EBV-driven LMP1 and IFN-γ up-regulate PD-L1 in nasopharyngeal carcinoma: Implications for oncotargeted therapy.
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.
authors.affiliation: 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.
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Fang
authors.affiliation: Department of Oncology, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Shaodong
authors.initials: S
authors.lastname: Hong
authors.affiliation: 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.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhan
authors.affiliation: Department of Oncology, the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Tao
authors.initials: T
authors.lastname: Qin
authors.affiliation: Department of Oncology, the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China.
authors.forename: Yanna
authors.initials: Y
authors.lastname: Tang
authors.affiliation: 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.
authors.forename: Yaxiong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Shiyang
authors.initials: S
authors.lastname: Kang
authors.affiliation: 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.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Xuan
authors.initials: X
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Liang
authors.affiliation: 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.
authors.forename: Zhihuang
authors.initials: Z
authors.lastname: Hu
authors.affiliation: 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.
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Ma
authors.affiliation: 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.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Ying
authors.initials: Y
authors.lastname: Tian
authors.affiliation: 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.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Cong
authors.initials: C
authors.lastname: Xue
authors.affiliation: 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.
authors.forename: Yue
authors.initials: Y
authors.lastname: Yan
authors.affiliation: 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.
authors.forename: Xue
authors.initials: X
authors.lastname: Hou
authors.affiliation: 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.
authors.forename: Peiyu
authors.initials: P
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Hongyun
authors.initials: H
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D060890:B7-H1 Antigen / Q000096:biosynthesis*; D015153:Blotting, Western; D002277:Carcinoma; D018572:Disease-Free Survival; D004797:Enzyme-Linked Immunosorbent Assay; D020031:Epstein-Barr Virus Infections / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D004854:Herpesvirus 4, Human; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000378:metabolism / Q000401:mortality / Q000821:virology*; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection; D015854:Up-Regulation; D014763:Viral Matrix Proteins / Q000378:metabolism*; D055815:Young Adult
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D034741:RNA, Small Interfering; D014763:Viral Matrix Proteins; D007371:Interferon-gamma