Prognostic value of soluble programmed cell death-1 (sPD-1) and soluble programmed cell death ligand-1 (sPD-L1) for hepatocellular carcinoma: a systematic review and meta-analysis

Abstract

Background: Preliminary studies have suggested that soluble programmed death-1 (sPD-1) and soluble programmed cell death ligand-1 (sPD-L1) have prognostic implications in many malignant tumors. However, the correlation between sPD-1/sPD-L1 level and prognosis of hepatocellular carcinoma (HCC) is still unclear.

Methods: We searched several electronic databases from database inception to October 7, 2021. Meta-analyses were performed separately for overall survival (OS), disease-free survival (DFS), recurrence-free survival (RFS), time to progression (TTP), and tumor-free survival (TFS). Random effects were introduced to this meta-analysis. The correlation between sPD-1/sPD-L1 level and prognosis was evaluated using hazard ratios (HRs) with 95% confidence intervals (95%CIs).

Results: A total of 11 studies (1291 patients) were incorporated into this meta-analysis, including seven on sPD-L1, two on sPD-1, and two about both factors. The pooled results showed that high sPD-L1 level was associated with worse OS (HR = 2.46, 95%CI 1.74-3.49, P < 0.001; I² = 31.4, P = 0.177) and poorer DFS/RFS/TTP/TFS of patients with HCC (HR = 2.22, 95%CI 1.47-3.35, P < 0.001; I² = 66.1, P = 0.011), irrespective of method of detection, study type, treatment, cut-off value and follow-up time. In contrast, the level of sPD-1 was not correlated to the OS (HR = 1.19, 95%CI 0.55-2.56, P = 0.657) and DFS/TFS of patients with HCC (HR = 0.94, 95%CI 0.36-2.49, P = 0.906).

Conclusion: sPD-L1 rather than sPD-1 could be a good predictor for recurrence and survival after treatment for HCC. More high-quality prospective studies are warranted to assess the prognostic value of sPD-1 or sPD-L1 for HCC.

Keywords: Hepatocellular carcinoma; Meta-analysis; Prognosis; sPD-1; sPD-L1.

Fig. 1

Study flow chart of the data extraction process and selection of studies for meta-analysis

Fig. 2

Forest plot of sPD-L1 in hepatocellular carcinoma. a Forest plot of sPD-L1 and OS in hepatocellular carcinoma. b Forest plot of sPD-L1 and DFS/RFS/TTP/TFS in hepatocellular carcinoma. CI, Confidence interval; HR, Hazard ratio; OS, Overall survival; sPD-L1, Soluble programmed cell death ligand-1; DFS, Disease-free survival; RFS, Recurrence-free survival; TTP, Time to progression; TFS, Tumor-free survival

Fig. 3

Funnel plots of sPD-L1 in hepatocellular carcinoma. a Funnel plots of HR for OS of sPD-L1. b Funnel plots of HR for DFS/RFS/TTP/TFS of sPD-L1. CI, Confidence interval; HR, Hazard ratio; OS, Overall survival; sPD-L1, Soluble programmed cell death ligand-1; DFS, Disease-free survival; RFS, Recurrence-free survival; TTP, Time to progression; TFS, Tumor-free survival

Fig. 4

Forest plot of sPD-1 in hepatocellular carcinoma. a Forest plot of sPD-1 and OS in hepatocellular carcinoma. b Forest plot of sPD-1 and DFS/TFS in hepatocellular carcinoma. CI, Confidence interval; HR, Hazard ratio; OS, Overall survival; sPD-L1, Soluble programmed cell death ligand-1; DFS, Disease-free survival; RFS, Recurrence-free survival; TTP, Time to progression; TFS, Tumor-free survival

Fig. 5

Sensitivity analysis of this meta-analysis. a Sensitivity analysis of OS. b Sensitivity analysis of DFS/RFS/TTP/TFS. CI, Confidence interval; HR, Hazard ratio; OS, Overall survival; sPD-L1, Soluble programmed cell death ligand-1; DFS, Disease-free survival; RFS, Recurrence-free survival; TTP, Time to progression; TFS, Tumor-free survival

Fig. 6

Assessment of publication bias for this meta-analysis using Begg’s test and Egger’s test. a Begg’s test for OS, P = 0.063. b Egger’s test for OS, P = 0.068. c Begg’s test for DFS/RFS/TTP/TFS, P = 1.000. d Egger’s test for DFS/RFS/TTP/TFS, P = 0.231. lnhr the ln of HR; s.e. standard error, OS, Overall survival, DFS, Disease-free survival; RFS, Recurrence-free survival; TTP, Time to progression; TFS, Tumor-free survival