Increased Expression of Programmed Death Ligand 1 in Hepatocellular Carcinoma of Patients with Hepatitis B Virus Pre-S2 Mutant

Chiao-Fang Teng; Tsai-Chung Li; Ting Wang; Tzu-Hua Wu; John Wang; Han-Chieh Wu; Woei-Cherng Shyu; Ih-Jen Su; Long-Bin Jeng

doi:10.2147/JHC.S282818

Increased Expression of Programmed Death Ligand 1 in Hepatocellular Carcinoma of Patients with Hepatitis B Virus Pre-S2 Mutant

J Hepatocell Carcinoma. 2020 Dec 17:7:385-401. doi: 10.2147/JHC.S282818. eCollection 2020.

Authors

Chiao-Fang Teng^{1

2

3}, Tsai-Chung Li^{4

5}, Ting Wang², Tzu-Hua Wu², John Wang⁶, Han-Chieh Wu⁷, Woei-Cherng Shyu^{1

8

9

10}, Ih-Jen Su¹¹, Long-Bin Jeng²

Affiliations

¹ Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
² Organ Transplantation Center, China Medical University Hospital, Taichung, Taiwan.
³ Research Center for Cancer Biology, China Medical University, Taichung, Taiwan.
⁴ Department of Public Health, College of Public Health, China Medical University, Taichung, Taiwan.
⁵ Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung, Taiwan.
⁶ Department of Pathology, China Medical University Hospital, Taichung, Taiwan.
⁷ National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan, Taiwan.
⁸ Department of Occupational Therapy, Asia University, Taichung, Taiwan.
⁹ Department of Neurology, China Medical University Hospital, Taichung, Taiwan.
¹⁰ Translational Medicine Research Center, China Medical University Hospital, Taichung, Taiwan.
¹¹ Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan.

Abstract

Purpose: Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC), a leading cause of cancer-related death worldwide. The HCC patients who harbor HBV pre-S2 mutant, an oncoprotein that plays key roles in HCC development, have been closely associated with a worse prognosis after curative surgical resection, suggesting an urgent need for alternative therapeutic options to improve their survival. In this study, we aimed to evaluate the expression profiles of programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1), two of the most well-studied immune checkpoint molecules that promote tumor immune evasion, in tumor of the pre-S2 mutant-positive/high HCC patients.

Methods: We classified 40 HBV-related HCC patients into the pre-S2-positive/high and -negative/low groups by a next-generation sequencing-based approach. The fluorescent immunohistochemistry staining was performed to detect the expression of PD-1 and PD-L1 in HCC tissues of patients.

Results: We showed that patients with either deletion spanning pre-S2 gene segment or high percentage of pre-S2 plus pre-S1+pre-S2 deletion (the pre-S2 mutant-positive/high group) exhibited a significantly higher density of PD-L1-positive cells in HCC tissues than those without. Moreover, the percentage of pre-S2 plus pre-S1+pre-S2 deletion displayed a high positive correlation with the density of PD-L1-positive cells in HCC tissues.

Conclusion: The increased expression of PD-L1 in tumor tissues of the pre-S2 mutant-positive HCC patients suggest that pre-S2 mutant may play a potential role in dysregulation of tumor immune microenvironment in the progression of HBV-related HCC, implicating for the development of future therapeutic strategies.

Keywords: hepatitis B virus; hepatocellular carcinoma; pre-S2 mutant; programmed death 1; programmed death ligand 1.