ULBP2 and RAET1E NKG2D ligands are independent predictors of poor prognosis in ovarian cancer patients

Abstract

The human activating immune receptor, NKG2D, binds to a diverse array of cellular ligands of the MIC and unique long 16 (UL16)-binding protein (ULBP)/retinoic acid early transcript (RAET) family. NKG2D is thought to participate in anticancer immune responses. By using tissue microarrays representing over 300 patients with defined clinicopathological factors, we present the first comprehensive screen of the expression of all NKG2D ligands in primary ovarian cancers. NKG2D ligands were expressed by the majority of tumors; however, the level of expression varied considerably. By categorizing each tumor as having negative, low or high expression, it was shown that high expression of several NKG2D ligands is inversely correlated with disease survival. Patients whose tumors had high expression of RAET1E (p 5 0.037), ULBP1 (p 5 0.036) and ULBP3 (p 5 0.004) surviving a median of 11, 14 and 11 months, respectively, compared with disease-specific survival of 29, 30 and 25 months in patients whose tumors showed no expression of these ligands. These results contrast with previous findings showing that high level NKG2D ligand expression is associated with good prognosis in colorectal cancer and suggest a fundamental difference in the involvement of NKG2D-mediated immunity in these two types of cancer. By using multivariate analysis, the factors retaining independent prognostic significance were International Federation of Gynecologists and Obstetricians stage (p < 0.001), presence of residual disease (p 5 0.003), ULBP2 (p 5 0.042) and RAET1E (p 5 0.030).Ovarian cancer is the second most common gynecological malignancy and the fourth most common cause of cancerrelated death in women in England and Wales, 1 with less than 10% of cases of ovarian cancer occurring in women under the age of 45 years. The 5-year survival rate of 30% improved little between 1950 and 1999. However, improvements in diagnosis and treatment in recent years are predicted to bring the 5-year survival up to 38% for women diagnosed after 2001. 1 The clinical factors of patient age, tumor stage and residual disease after surgical debulking are standard predictors of prognosis but do not account for the variation seen between apparently similar tumors when using these variables.There is now increasing evidence that the immune system may have a role to play in controlling tumor development and growth. 2 In multivariate analysis on prognostic factors in ovarian cancer, several groups have shown that the presence or absence of intratumoral T cells [3][4][5] and, in particular, cytotoxic T cells 6,7 was an independent predictor of enhanced survival. In contrast, the presence of intratumor regulatory T cells was associated with a poor prognosis. 8,9 Studies with in vivo cancer models strongly suggest that the activating immune receptor NKG2D is involved in anticancer immune responses. [10][11][12][13][14] In humans, both primary tumors and tumor derived cell lines frequently express NKG2D ligands. [15][16][17] The C-type lectin-like receptor NKG2D is unique among...

Immunohistochemical Validation and Expression Profiling of NKG2D Ligands in a Wide Spectrum of Human Epithelial Neoplasms

“…Immunohistochemistry for NKG2D ligands consistently demonstrated a predominantly diffuse cytoplasmic and partial membranous staining pattern, as reported previously McGilvray et al 2010;McGilvray et al 2009;Eagle et al 2009a;Eagle et al 2009b). Among nonneoplastic tissues, there were several patterns of NKG2D ligand expression.…”

“…Many reports have already described the expression of MICA/B in a broad range of normal and tumor tissues in humans, including various carcinomas (breast, lung, colon, kidney, ovary and prostate), leukemias, gliomas, neuroblastomas and melanomas Vetter et al 2002;Friese et al 2003;Salih et al 2003;Watson et al 2006;Castriconi et al 2007). Similarly, it has been reported that ULBPs are expressed in several types of human tumors, and that up-regulation of NKG2D ligands in cancer is associated with patient survival (McGilvray et al 2010;McGilvray et al 2009). Moreover, recent studies have strongly suggested that the expression levels of these ligands are associated with enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) activity (Inagaki et al 2009), which is one of the key mechanisms responsible for the antitumor effect of antibody therapeutics.…”

The human NKG2D ligand ULBP2 can be expressed at the cell surface with or without a GPI anchor and both forms can activate NK cells

“…For example, high tumour expression of MIC and/or ULBPs was associated with improved patient survival in colorectal cancer (McGilvray et al, 2009), whereas in ovarian cancer, high expression of several NKG2D ligands was inversely correlated with patient survival (McGilvray et al, 2010). Analysis of the NKG2D system in disease is complex because of the large number of distinct ligands for a single receptor and the possibility of regulation by released soluble ligands.…”

MALDI-MSI and Ovarian Cancer Biomarkers

“…Transcriptomic studies have shown the over-expression of the macrophage migration inhibitory factor (MIF) 62,63 , Receptorbinding cancer antigen expressed on SiSo cells 64 known to be implicated in lymphocytes apoptosis. MIF contributes to the inhibition of antitumoral CD8+ T and NK cells by downregulation of NKG2D (NK cell receptor NK group 2D) 65 . From our MALDI-MSI studies, five factors involved in immune response modulation in mucinous tumors have been identified, namely a C-terminal fragment of the 11S immunoproteasome (Reg-alpha) (Figure 3), orosomucoid, apolipoprotein A1, hemopexin, and lumican which have also been detected in ascites 1,5,7,36,37 .…”