Pre-treatment serum levels of soluble programmed cell death-ligand 1 predict prognosis in patients with hepatitis B-related hepatocellular carcinoma
Anti-programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) therapy has shown promise in tumor immunotherapy. Our objectives were to measure pre-treatment serum-soluble PD-L1 (sPD-L1) levels and to assess the relationships between sPD-L1 levels and clinical characteristics, prognosis, and tumor tissue PD-L1 expression in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC).
Pre-treatment serum sPD-L1 levels were measured with an enzyme-linked immunosorbent assay (ELISA) in 81 patients with HBV-related HCC and compared to those in 49 healthy controls. The association between serum sPD-L1 levels and prognosis was assessed using survival analysis. The correlation between paired serum sPD-L1 levels and tumor PD-L1 expression (in resected tissue homogenates) was assessed in a separate group of 20 patients with HBV-related HCC.
Median sPD-L1 concentration in patients with HBV-related HCC was 5.129 (range 0.140–12.391) ng/mL and in healthy controls was 0.836 (range 0.105–2.168) ng/mL (p < 0.001). On multivariate analysis, sPD-L1 levels were significant independent predictors of disease-free survival (hazard ratio [HR] 3.503; 95% confidence interval [CI], 1.559–7.871; p = 0.002) and overall survival (HR 3.399; 95% CI 1.308–8.831; p = 0.012). Positive correlation (r = 0.527, p = 0.017) between serum sPD-L1 and tumor PD-L1 expression was observed. Tumor expression of PD-L1 was significantly higher in those with serum sPD-L1 concentrations above vs. below the median level of 5.471 ng/ml (p = 0.012).
In patients with HBV-related HCC, serum sPD-L1 concentrations were elevated, and positively correlated with tumor PD-L1 expression. Lower pre-treatment serum sPD-L1 levels were predictors of more favorable disease-free and overall survival. Serum sPD-L1 testing has a potential role in HBV-related HCC disease assessment, systemic therapy choices and survival prediction.
KeywordsHBV-related hepatocellular carcinoma Hepatitis B virus PD-L1 Prognosis Soluble PD-L1
Programmed cell death-1
Programmed cell death-ligand 1
Hepatitis B virus
Modified response evaluation criteria in solid tumors
Enzyme-linked immunosorbent assay
European Association for the Study of the Liver
Tumor, node, metastases
Barcelona Clinic Liver Cancer
Cancer of the Liver Italian Program
JH, QC, and YG contributed to the conception and design of the study. XH, MZ and JH drafted and reviewed the manuscript. XH, SL, HC and HD participated in data collection and performed the experiments. Min-shan Chen provided the patients’ specimen. YG and XH contributed to the data analysis and interpretation. All authors have read and approved the final manuscript.
The design of the study was supported by the National Natural Science Foundation of China under Grant [no. 81771955]; the Guangzhou Science and Technology Program (key projects of collaborative innovation of health medicine) under Grant [no. 201704020228]; and the Guangzhou Science and Technology Program (key projects of collaborative innovation of production, learning and research) under Grant [no. 201704020134]; Sun Yat-sen University Clinical Trial 5010 Project under Grant [no. 2016002].
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
The study was approved by the Institutional Review Committee of Sun Yat-sen University Cancer Centre in Guangzhou, China (YB2015-018-01). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Written informed consent for procedures was obtained from patients and families. All procedures were performed after obtaining informed consent in accordance with the approved protocol.
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