Overexpression of PD-L1 and PD-L2 Is Associated with Poor Prognosis in Patients with Hepatocellular Carcinoma

Abstract

Purpose: Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies. Recently, the overexpression of programmed cell death 1 (PD-1) and PD-1 ligand 1 (PD-L1) has been shown to correlate with poor prognosis in many cancers. However, the expression of PD-L1 or PD-1 ligand 2 (PD-L2) and clinical outcomes have not been fully investigated in HCC.

Materials and methods: Formalin-fixed paraffin-embedded samples were obtained from 85 patients with HCC who underwent surgery. The expression of PD-Ls (PD-L1, PD-L2) was evaluated by immunohistochemical analysis.

Results: The proportion of high expression groups of PD-L1 and PD-L2 was 27.1% and 23.5%, respectively. Univariate analysis revealed that tumor size (p < 0.001), histological differentiation (p=0.010), PD-L1 expression (p < 0.001), and PD-L2 expression (p=0.039) were significant prognostic factors of overall survival in patients with HCC. Multivariate analysis revealed that overall tumor size (hazard ratio [HR], 4.131; 95% confidence interval [CI], 2.233 to 7.643; p < 0.001 and HR, 3.455; 95% CI, 1.967 to 6.067; p < 0.001) and PD-L1 expression (HR, 5.172; 95% CI, 2.661 to 10.054; p < 0.001 and HR, 3.730; 95% CI, 1.453 to 9.574; p=0.006) were independent prognostic values for overall and disease-free survival. Patients with high expression of PD-Ls had a significantly poorer survival than those with low expression (p < 0.001, p=0.034).

Conclusion: The overexpression of PD-Ls in HCC patients is correlated with survival and tumor recurrence. Further evaluation of PD-1 and PD-Ls as therapeutic targets and predictive biomarkers for HCC is warranted.

Keywords: Hepatocellular carcinoma; Prognosis; Programmed cell death 1; Programmed cell death 1 ligand.

Fig. 1.

Immunohistochemical staining of hepatocellular carcinoma tissues using anti–PD-L1 and anti–PD-L2 antibodies. (A-H) Representative staining patterns of hepatocellular carcinoma with negative (A, E), weak intensity (B, F), moderate intensity (C, G), and strong intensity (D, H) staining of PD-L1 (A-D) and PD-L2 (F-H) are shown (×200). PD-L, programmed cell death 1 ligand.

Fig. 2.

Kaplan-Meier survival curves for disease-free survival and overall survival according to PD-L1 (A, B), PD-L2 (C, D), and their combined (E, F) expression status.