Epstein-Barr Virus LMP1 Induces Soluble PD-L1 in Nasopharyngeal Carcinoma.

Kina Kase,Eiji Kobayashi,Takeshi Komori,Nobuyuki Hirai,Harue Mizokami,Tomokazu Yoshizaki,Naohiro Wakisaka,Makiko Moriyama-Kita,Makoto Kano,Kazuhira Endo,Hirotomo Dochi,Satoru Kondo,Hisashi Sugimoto,Miyako Hatano,Yosuke Nakanishi,Takayoshi Ueno

doi:10.3390/microorganisms9030603

Kina Kase, Eiji Kobayashi + Show 14 more

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https://doi.org/10.3390/microorganisms9030603

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Journal: Microorganisms	Publication Date: Mar 15, 2021
Citations: 11	License type: CC BY 4.0

Affiliation: Kanazawa University

Abstract

Nasopharyngeal carcinoma (NPC) is an Epstein–Barr virus (EBV)-associated malignancy. The principal oncogene of EBV, latent membrane protein 1 (LMP1), induces the expression of programmed death-ligand 1 (PD-L1), which is an immunosuppressive transmembrane protein and a promising therapeutic target for various malignancies. Recent studies have revealed an association between the level of soluble PD-L1 (sPD-L1) and disease progression. However, the role of sPD-L1 in NPC or its relevance to LMP1 has not been elucidated. This study aimed to examine whether LMP1 induces sPD-L1 in vitro and analyze the clinical relevance of LMP1, PD-L1, and sPD-L1 in NPC patients. Analysis of nasopharyngeal cell lines revealed that LMP1 induces both cellular PD-L1 and sPD-L1. Analysis of biopsy specimens from 32 NPC patients revealed that LMP1 expression was significantly correlated with PD-L1 expression. Finally, the serum sPD-L1 level in NPC patients was higher than that in the controls. Moreover, the sPD-L1 level in the advanced stage was higher than that in the early stage. However, LMP1 expression, PD-L1 expression, and sPD-L1 levels were not associated with prognosis. These results suggest that LMP1 induces both sPD-L1 and PD-L1, which are associated with NPC progression.

Highlights

Epstein–Barr virus (EBV) is strongly associated with the etiology of nasopharyngeal carcinoma (NPC) [1,2]
Fang et al reported that Latent membrane protein 1 (LMP1) induces cellular Programmed death ligand 1 (PD-L1) expression in NPC cell lines [8]
LMP1-expressing NP69T cells (NP69T-LMP1) compared with that in NP69T cells (Figure 1). This result indicates that LMP1 induced the expression of the PD-L1 protein

Summary

Introduction

Epstein–Barr virus (EBV) is strongly associated with the etiology of nasopharyngeal carcinoma (NPC) [1,2]. Latent membrane protein 1 (LMP1), a principal oncogene of EBV [3], contributes to the promotion of invasion and metastasis as well as initial oncogenesis of NPC [4]. LMP1 promotes escape from various immune recognition processes, especially cytotoxic T lymphocyte response that kills tumor cells and virus-infected cells [5]. Programmed death ligand 1 (PD-L1), a transmembrane glycoprotein, binds to PD-1 on T lymphocytes and suppresses T lymphocyte activation [6]. Tumor cells express PD-L1 and utilize the PD-L1/PD-1 checkpoint for immune evasion [7]. Fang et al reported that LMP1 induced cellular PD-L1 expression in vitro, and their data confirmed that blocking both

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