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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2016

Open Access 01-12-2016 | Research

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

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

Published in: Journal of Hematology & Oncology | Issue 1/2016

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Abstract

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.
Appendix
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Metadata
Title
PD-L1 is upregulated by EBV-driven LMP1 through NF-κB pathway and correlates with poor prognosis in natural killer/T-cell lymphoma
Authors
Xi-wen Bi
Hua Wang
Wen-wen Zhang
Jing-hua Wang
Wen-jian Liu
Zhong-jun Xia
Hui-qiang Huang
Wen-qi Jiang
Yu-jing Zhang
Liang Wang
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2016
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-016-0341-7

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