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

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.

Expression and prognostic significance of unique ULBPs in pancreatic cancer

“…Taken together, the results of our experiments confirm the idea that m-ULBPs (membrane NKG2D ligands) are involved in the antitumor immune response, and high levels of s-ULBPs (soluble NKG2D ligands) are correlated with a poor prognosis of patients 37. This is supported by the fact that s-ULBP2 was shown to be a novel serum marker for identification of PC 19. Similarly, Cho et al showed that m-ULBP1–5 were all expressed in cervical cancer tissue and that m-ULBP1 was an independent predictor of good prognosis regarding both DFS and OS 19.…”

A functional polymorphism in the NKG2D gene modulates NK-cell cytotoxicity and is associated with susceptibility to Human Papilloma Virus-related cancers

“…In addition to acquired immune responses, innate immune responses, including mucosal defense and particularly NK cells, have an active and important role35. A potential role of NK cells in eliminating HPV-transformed cells is supported by the observations that NKG2D-Ls expression, including ULBP1, MICA/B and ULBP2, in cervical cancer specimens was found to be an indicator of good prognosis in patients with cervical cancer, suggesting that ligand-expressing cells can be targeted by NKG2D receptor-expressing immune cells in vivo 36. In addition, cervical cancer cell lines express NKG2D-Ls and interact with NKG2D-expressing NK cells in vitro 37.…”

Prognostic significance and functional implication of immune activating receptor NKG2D in gastric cancer

“…Many studies have reported that expression of NKG2D ligands was associated with the prognosis of patients with cancer [13,14]. Recently, Chen et al [15] found that high NKG2D expression was significantly associated with increased DFS and OS of the patients with pancreatic cancer, but NKG2D was not an independent prognostic factor.…”