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Programmed death ligand 1 expression in human intrahepatic cholangiocarcinoma and its association with prognosis and CD8+ T-cell immune responses

Authors Zhu Y, Wang XY, Zhang Y, Xu D, Dong J, Zhang Z, Yi CH, Jia HL, Yang X

Received 1 May 2018

Accepted for publication 22 June 2018

Published 2 October 2018 Volume 2018:10 Pages 4113—4123

DOI https://doi.org/10.2147/CMAR.S172719

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Andrew Yee

Peer reviewer comments 2

Editor who approved publication: Professor Nakshatri


Ying Zhu,1,2,* Xiang-Yu Wang,1,2,* Yu Zhang,1,2,* Da Xu,1,2,* Jian Dong,3,4 Ze Zhang,1,2 Chen-He Yi,1,2 Hu-Liang Jia,1,2 Xin Yang1,2

1Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China; 2Institutes of Cancer Metastasis, Fudan University, Shanghai 200040, China; 3Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi’an Jiaotong University, Xi’an 710061, China; 4Institute of Advanced Surgical Technology and Engineering, First Affiliated Hospital of Medical College, Xi’an Jiaotong University, Xi’an 710061, China

*These authors contributed equally to this work

Background: Agents targeting the programmed death ligand 1 (PD-L1)/programmed death receptor 1 immune checkpoint exhibited promising clinical outcomes in a variety of malignant tumors, including intrahepatic cholangiocarcinoma (ICC). However, the relationship between PD-L1 expression and CD8+ T-cell immune responses is not well defined in ICC.
Patients and methods: We investigated PD-L1 expression immunohistochemistry in formalin-fixed, paraffin-embedded tissues from 192 ICC patients undergoing curative resection and correlated our results with the clinicopathologic features and prognosis. We also quantified CD8+ T-cell infiltration in ICC specimens and evaluated the relationship between PD-L1 expression and CD8+ T-cell infiltration. After incubating human ICC cell lines (HCCC9810 and RBE) with interferon (IFN)-γ, we measured the PD-L1 expression of these ICC cells by Western blot and flow cytometry.
Results: Only 34 patients (17.7%) showed ≥5% membranous PD-L1 expression on tumor cells, and tumoral PD-L1 overexpression (≥5%) was significantly associated with superior overall survival (P=0.012) and disease-free survival (P=0.018). A significant positive association was found between PD-L1 expression and the presence of CD8+ T-cells. In fresh frozen ICC specimens, IFN-γ was found to be significantly correlated with PD-L1 and CD8A gene expression, as evaluated by reverse transcription-polymerase chain reaction. Moreover, stimulation of the HCCC9810 and RBE cells with recombinant IFN-γ, secreted by CD8+ T-cells rapidly induced PD-L1 upregulation in these cell lines in vitro.
Conclusion: Tumor PD-L1 overexpression is mainly stimulated by activated CD8+ T-cells pre-existing in the ICC microenvironment, and PD-L1 is a favorable prognostic factor for the patients. These observations suggest that anti-PD-L1/programmed death receptor 1 therapy may benefit ICC patients with tumor cell PD-L1 expression and the presence of CD8+ T-cells.

Keywords: tumor microenvironment, adaptive immune resistance, PD-L1, CD8+ T-cell, IFN-γ

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