Overexpression of natural killer group 2 member D ligands predicts favorable prognosis in cholangiocarcinoma

Abstract

The natural killer group 2 member D (NKG2D) receptor and its ligands are important mediators of immune responses to tumors. NKG2D ligands are overexpressed in several malignant tumor types; however, the prognostic value of these ligands is unclear. Here, we aimed to elucidate the role of NKG2D ligands in extrahepatic cholangiocarcinoma (EHCC). We therefore investigated the expression of the NKG2D receptor and its ligands MHC class I chain-related proteins A and B (MICA ⁄ B), unique long 16 binding protein (ULBP) 1, and ULBP2 ⁄ 5 ⁄ 6 in resected specimens from 82 patients with EHCC. All NKG2D ligands were highly expressed in EHCC. High expression of MICA ⁄ B or ULBP2 ⁄ 5 ⁄ 6 correlated with overall and disease-free survival. In contrast, high expression of ULBP1 was significantly associated with improved overall survival, but not disease-free survival. Concurrent high expression of multiple NKG2D ligands revealed significantly better overall and disease-free survival than that observed with the overexpression of any one NKG2D ligand. Co-expression of multiple NKG2D ligands was an independent prognostic indicator of improved survival. Furthermore, co-overexpression of multiple NKG2D ligands was significantly correlated with high expression of the NKG2D receptor. Inhibiting interactions between multiple NKG2D ligands and the NKG2D receptor might be a promising approach for controlling cancer progression and improving patient prognosis in EHCC.C holangiocarcinoma is a malignant cancer that originates from epithelial cells in bile ducts.(1,2) It is classified as intrahepatic or extrahepatic, and EHCC is subcategorized into perihilar and distal forms. (3,4) Although EHCC is relatively uncommon in North America and Europe, its incidence and mortality rates continue to rise worldwide. (5,6) This is especially true in Japan, where the annual mortality due to EHCC was approximately 12 000 in 2013.(7) There is no curative treatment for cholangiocarcinoma except surgical resection and, despite recent advances in surgical techniques, recurrence occurs in most patients even after resection. Regrettably, post-resection 5-year survival rates are only 20-30%.(8) Therefore, the identification of new therapeutic targets and biomarkers is critical for improving outcomes in patients with cholangiocarcinoma.We previously reported that epithelial-mesenchymal transition-related factors, such as epithelial ⁄ neural-cadherin and forkhead box protein C2, were correlated with the prognosis and progression of EHCC.(9,10) Due to recent advancements in cancer immunotherapeutics, the editors of Science named cancer immunotherapy as the Breakthrough of the Year in 2013.(11) In particular, the immune checkpoint blockade approach involving the use of the anti-cytotoxic T-lymphocyte antigen 4 antibody and the anti-PD-1 antibody were significant recent developments. The US FDA has approved ipilimumab, pembrolizumab, and nivolumab for the treatment of metastatic melanoma, and the Pharmaceuticals and Medical Devices Agency in Japan has approved nivol...

Immune Therapy for Liver Cancers

“…Knowledge about the BTC immune microenvironment remains scarce and needs to be further characterized [79]. Immunohistochemistry studies showed an association between CD8-positive TILs, natural killer lymphocytes, and major histocompatibility complex class I expression and prolonged survival; whereas M2-macrophage and neutrophil infiltrates were associated with early recurrence and death; and T regulatory cells (FOXP3-positive) showed inconsistent prognostic value [16,[80][81][82][83][84]. Although poorly represented in the TCGA initiative [85], BTCs seems to be rich in immune cells in 70% of cases and depleted in lymphocytes in 30%.…”

Activation or suppression of the immune response mediators in biliary tract cancer (BTC) patients: a systematic review and meta-analysis

“…In comparison, intraepithelial tumor-infiltrating CD4+, CD8+, and Foxp3+ T lymphocytes, MHC I and NKG2D were referred as positive factors to prolong the overall survival of patients with BTC. The role of intraepithelial tumor-infiltrating CD8+ T lymphocytes, MHC I and NKG2D has been identified and reported a beneficial prognostic effect of high cell counts in a variety of human malignancies including BTC 8, 9, 11, 12, 27, 30-32. Goepport also found a better prognostic impact of both intraepithelial tumor-infiltrating CD4+ and Foxp3+ T lymphocytes.…”

“…Studies identified immune cell types or ratio including CD4+, CD8+, and Foxp3+ Tumor-infiltrating T lymphocytes (TILs), IL17+, neutrophil recruitment (CD66b+), PD-1/CD8 TILs and neutrophil/lymphocyte (NLR), and analyzed the distribution and clinical relevance of these mediators 8, 10, 12-14. Others observed the impact of the expression of major histocompatibility complex class I (MHC I) and natural killer group 2 member D (NKG2D) 9, 11.…”

Immunobiology of cholangiocarcinoma

“…53 In contrast, high expression of NKG2D ligands in human CCA are associated with improved disease-free and overall patient survival, implying that treatment strategies that encourage interaction between NKG2D and its ligand may be a promising therapeutic approach in CCA. 54 Preclinical data from studies assessing therapeutic strategies that augment NK cell activity in CCA are encouraging, albeit limited. Co-culture of CCA cells with the epidermal growth factor receptor monoclonal antibody, cetuximab, and NK cells significantly enhanced CCA cell death by potentiating antibodydependent cellular cytotoxicity.…”