MICA/B and ULBP1 NKG2D ligands are independent predictors of good prognosis in cervical cancer.

Hanbyoul Cho,Jae-Hoon Kim,Jennie Kim,Joon-Yong Chung,Eun Joo Chung,Till Braunschweig,Tae Heung Kang,Stephen M Hewitt,Sunghoon Kim

doi:10.1186/1471-2407-14-957

Abstract

BackgroundNKG2D (natural killer group 2, member D) is thought to play an important role in mediating the activation of anticancer immune response. Expression of NKG2D ligands (NKG2DLs) is pronounced in malignancies and the heterogeneity of NKG2DL expression remains unclear. Here, we investigate the expression and clinical significance of NKG2DLs in cervical cancer.MethodsImmunohistochemical analyses of MICA/B, ULBP1, ULBP2, ULBP3, RAET1E, and RAET1G were performed using tissue microarray analysis of 200 cervical cancers, 327 high-grade cervical intraepithelial neoplasias (CINs), 99 low-grade CINs, and 541 matched nonadjacent normal cervical epithelial tissues and compared the data with clinicopathologic variables, including the survival of cervical cancer patients.ResultsMICA/B, ULBP1, and RAET1E expression was higher in cervical cancer than in low-grade CIN (p < 0.001, p = 0.012, p = 0.013, respectively) and normal cervix (all p < 0.001). Among these markers, expression of ULBP1 was significantly different depending on patient tumor stage (p = 0.010) and tumor size (p = 0.045). ULBP1 expression was correlated with MICA/B (p < 0.001) and ULBP2 (p = 0.002) expression in cervical cancer. While MICA/B+ or ULBP1+ patients had improved disease-free survival time (p = 0.027 and p = 0.009, respectively) relative to that of the low expression group, RAET1E+ or RAET1G+ was correlated with shorter survival time (p = 0.018 and p = 0.029, respectively). However, in terms of overall survival, the ULBP1+ group had significantly longer survival time than the low expression group (p = 0.009). Multivariate analysis indicated that MICA/B+/ULBP1+ (HR = 0.16, p = 0.015) and ULBP1+ (HR = 0.31, p = 0.024) are independent prognostic factors of disease-free survival in cervical cancer.ConclusionsHigh expression of either ULBP1 or MICA/B and ULBP1 combined is an indicator of good prognosis in cervical cancer, suggesting their potential utility as prognostic tests in clinical assessment.

Highlights

NKG2D is thought to play an important role in mediating the activation of anticancer immune response
We investigated the expression of MICA/B, ULBP1, ULBP2, ULBP3, RAET1E, and RAET1G in normal cervical epithelium and cervical neoplasia in a large series of formalin-fixed, paraffin-embedded tumor samples made by using high-throughput tissue microarray (TMA) technology
Because Human papillomavirus (HPV) is associated with cervical carcinogenesis, we examined the relationship between HPV status and NKG2D ligand (NKG2DL) expression in cervical neoplasia

Summary

Introduction

NKG2D (natural killer group 2, member D) is thought to play an important role in mediating the activation of anticancer immune response. Persistent infection with one of the high-risk forms of human papillomavirus Natural killer (NK) cells are important cytolytic and cytokine-producing effector cells of the innate immune system. These cells have the ability to attack tumor cells and cells infected with viruses and some bacteria without presentation of tumorspecific antigens [7]. In the case of cervical cancer, Garzetti et al reported that NK cell activity was related to prognostic parameters and clinical outcome [10]

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