Journal Article

PD-L1 is upregulated by EBV-driven LMP1 through NF-κB pathway and correlates with poor prognosis in natural killer/T-cell lymphoma

Wang, Jing-hua, Zhang, Yu-jing, Huang, Hui-qiang, Liu, Wen-jian, Xia, Zhong-jun, Zhang, Wen-wen, Jiang, Wen-qi, Bi, Xi-wen, Wang, Liang, Wang, Hua

2016

Overview

Background Natural killer/T-cell lymphoma (NKTCL) is an Epstein–Barr virus (EBV)-associated, highly aggressive lymphoma. Treatment outcome remains sub-optimal, especially for advanced-stage or relapsed diseases. Programmed cell death receptor 1 (PD-1) and PD ligand 1 (PD-L1) have become promising therapeutic targets for various malignancies, but their role in the pathogenesis and their interactions with EBV in NKTCL remains to be investigated. Methods Expression of PD-L1 was measured in NK-92 (EBV-negative) and SNK-6 (EBV-positive) cells by western blot, quantitative real-time PCR and enzyme-linked immunosorbent assay, and flow cytometry, respectively. Latent membrane protein 1 (LMP1)-harboring lentiviral vectors were transfected into NK-92 cells to examine the correlation between LMP1 and PD-L1 expression. Proteins in the downstream pathways of LMP1 signaling were measured in NK-92 cells transfected with LMP1-harboring or negative control vectors as well as in SNK-6 cells. PD-L1 expression on tumor specimens and serum concentration of soluble PD-L1 were collected in a retrospective cohort of patients with Ann Arbor stage I~II NKTCL, and their prognostic significance were analyzed. Results Expression of PD-L1 was significantly higher in SNK-6 cells than in NK-92 cells, at both protein and mRNA levels. Expression of PD-L1 was remarkably upregulated in NK-92 cells transfected with LMP1-harboring lentiviral vectors compared with those transfected with negative control vectors. Proteins in the MAPK/NF-κB pathway were upregulated in LMP1-expressing NK-92 cells compared with the negative control. Selective inhibitors of those proteins induced significant downregulation of PD-L1 expression in LMP1-expressing NK-92 cells as well as in SNK-6 cells. Patients with a high concentration of serum soluble PD-L1 (≥3.4 ng/ml) or with a high percentage of PD-L1 expression in tumor specimens (≥38 %) exhibited significantly lower response rate to treatment and remarkably worse survival, compared with their counterparts. A high concentration of serum soluble PD-L1 and a high percentage of PD-L1 expression in tumor specimens were independent adverse prognostic factors among patients with stage I~II NKTCL. Conclusions PD-L1 expression positively correlated LMP1 expression in NKTCL, which was probably mediated by the MAPK/NF-κB pathway. PD-L1 expression in serum and tumor tissues has significant prognostic value for early-stage NKTCL.

• Publisher: BioMed Central,BMC
• Subject: B7-H1 Antigen - analysis / B7-H1 Antigen - blood / Biopsy / Cancer Research / Cells, Cultured / Epstein–Barr virus / Female / Gene Expression Regulation, Neoplastic / Hematology / Herpesvirus 4, Human / Host-Pathogen Interactions / Humans / Latent membrane protein 1 / Lymphoma, Extranodal NK-T-Cell - diagnosis / Lymphoma, Extranodal NK-T-Cell - pathology / Lymphoma, Extranodal NK-T-Cell - virology / Male / Medicine / Medicine & Public Health / Middle Aged / Natural killer/T-cell lymphoma / NF-kappa B - metabolism / Oncology / Prognosis / Programmed cell death receptor 1 / Transfection / Viral Matrix Proteins - genetics / Viral Matrix Proteins - physiology