Decreased expression of the NKG2D ligand ULBP4 may be an indicator of poor prognosis in patients with nasopharyngeal carcinoma.

Yuanji Xu,Lin Zhou,Sufang Qiu,Qiaojuan Guo,Honglin Chen,Jianji Pan,Gang Chen,Jingfeng Zong,Shaojun Lin,Yanping Chen,Xuehong Liao,Yunbin Ye

doi:10.18632/oncotarget.14917

Abstract

U16-binding protein 4 (ULBP4), a human ligand for natural killer group 2, member D (NKG2D) receptor on NK cells and subsets of T cells, is thought to activate anticancer immune responses. However, the expression pattern and prognostic effect of ULBP4 in nasopharyngeal carcinoma (NPC) has not been investigated. We first compared ULBP4 expression between archival 15 NPC tissues and 8 normal nasopharynx (NP) tissues using qPCR. Then ULBP4 expression among 111 NPC specimens was validated on immunohistochemical examination. In addition, the association of ULBP4 expression with clinical characteristics and survival outcomes was analyzed. Furthermore, the impact of ULBP4 expression in NPC cells on the cytotoxic activity of NK cells was investigated. Both mRNA and protein ULBP4 expressions of NPC tissues were significantly lower than those in normal NP tissues. However, no association of ULBP4 expression with clinical characteristics was observed. Patients with NPC having decreased expression of UBLP4 had significantly poorer overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival (DMFS) than those with preserved levels of ULBP4. On multivariate analyses, low expression of ULBP4 was of borderline significance for OS, PFS, and DMFS (P = 0.060, 0.053, and 0.076, respectively). Further, LDH analysis demonstrated that the cytotoxic activitity of NK cells against C666-1 or 5-8F NPC cells with lenti-ULBP4 was considerably increased as compared to those with lenti-vector at various E/T ratios. Hence, restoration of ULBP4 expression may be a novel therapeutic strategy for treatment of NPC. However, further study is required to confirm these findings.

Highlights

Nasopharyngeal carcinoma (NPC) is regarded as the most common head and neck cancer in SoutheastAsia, especially in Southern China, with the incidence approaching 30 per 100,000 person-years [1]
This is the first study to explore the pattern of ULBP4 expression and its prognostic value in patients with nasopharyngeal carcinoma (NPC)
ULBP4 was found to be significantly downregulated in primary NPC tissues when compared with normal NP tissues at both mRNA and protein levels

Summary

Introduction

Nasopharyngeal carcinoma (NPC) is regarded as the most common head and neck cancer in Southeast. Especially in Southern China, with the incidence approaching 30 per 100,000 person-years [1]. The current consensus on treatment includes early treatment with radiotherapy alone, and concurrent chemotherapy www.impactjournals.com/oncotarget combined with radiotherapy for locally advanced disease. The 5-year overall survival (OS) rate for early stage NPC can exceed 90% with use of intensitymodulated radiotherapy (IMRT) [2]. For locally advanced NPC, OS rates of 78.4%-80% have been reported with a combination of IMRT and chemotherapy [3, 4]. 20%~30% of patients with NPC develop treatment failure and distant metastasis [5, 6]. It is necessary to explore novel therapeutic modalities to treat patients with NPC

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Results

Conclusion