Prognostic impact of programmed cell death ligand 1 (PD-L1) expression and its association with epithelial-mesenchymal transition in extrahepatic cholangiocarcinoma
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Takashi Ueno1,2, Takahiro Tsuchikawa1, Kanako C. Hatanaka2, Yutaka Hatanaka2, Tomoko Mitsuhashi2, Yoshitsugu Nakanishi1, Takehiro Noji1, Toru Nakamura1, Keisuke Okamura1, Yoshihiro Matsuno2 and Satoshi Hirano1
1Department of Gastroenterological Surgery II, Division of Surgery, Faculty of Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
2Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Hokkaido, Japan
Takahiro Tsuchikawa, email: [email protected]
Keywords: extrahepatic cholangiocarcinoma; PD-L1; tumor infiltrating lymphocytes; epithelial-mesenchymal transition; immunohistochemical analysis
Received: July 20, 2017 Accepted: March 21, 2018 Published: April 13, 2018
Extrahepatic cholangiocarcinoma (eCCA) has a poor prognosis. Although the possibility of immunotherapy has been studied, immune checkpoint molecules such as programmed death ligand 1 (PD-L1) in eCCA are not well understood. Epithelial-mesenchymal transition (EMT) has recently been shown to regulate PD-L1 expression. Our aims were to assess the clinicopathological significance of tumor-infiltrating lymphocytes (TILs) and tumor PD-L1 expression in eCCA and to compare these immune responses with EMT marker expression. In this retrospective study, we conducted immunohistochemical analyses for 117 patients with eCCA. We stained for CD4, CD8, Foxp3, and PD-L1 as markers reflecting local immune responses, and for E-cadherin, N-cadherin, vimentin, ZEB1, ZEB2, SNAIL, and TWIST as markers associated with EMT. High numbers of CD4+ and CD8+ TILs correlated with node-negative (P = 0.009 and P = 0.046, respectively) and low SNAIL expression (P = 0.016 and P = 0.022, respectively). High PD-L1 expression was associated with poor histopathological classification (P = 0.034), and low E-cadherin (P = 0.001), high N-cadherin (P = 0.044), high vimentin (P < 0.001) and high ZEB1 (P = 0.036) expression. Multivariate analysis showed that CD4+ TILs, PD-L1 expression and N-cadherin expression were independent prognostic factors (hazard ratio (HR) = 0.61; 95% confidence interval (CI) = 0.38–1.00; HR=4.27; 95% CI = 1.82–9.39; HR = 2.20; 95% CI = 1.18–3.92, respectively). These findings could help to identify potential biomarkers for predicting not only the prognosis, but also the therapeutic response to immunotherapy for eCCA.
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