Positive Expression of Programmed Death Ligand 1 in Peritumoral Liver Tissue is Associated with Poor Survival after Curative Resection of Hepatocellular Carcinoma

Abstract

BACKGROUND: Recurrence or metastasis of hepatocellular carcinoma (HCC) is mainly intrahepatic after curative resection, demonstrating that the peritumoral environment is important but often neglected. Programmed death ligand 1 (PD-L1) in intratumoral liver tissues is a poor prognosis factor whose impact is removed after curative resection. However, PD-L1 expression remains in the peritumoral liver tissues and its distribution and prognostic value are still not clear. METHODS: We assessed the expression of PD-L1 by immunohistochemistry in peritumoral liver tissues from 90 HCC patients who underwent curative hepatectomy. The results were validated in an independent cohort of additional 90 HCC patients. RESULTS: We found PD-L1 positive expression in 31.11% (28/90) of peritumoral tissues. Peritumoral PD-L1 expression was associated with a significantly worse overall survival (OS) (P = .000) and disease-free survival (DFS) (P = .001) compared to the negative expression group. Additionally, peritumoral PD-L1 positivity significantly correlated with vascular invasion and a lower albumin level (≤35 g/L). Univariate and multivariate Cox regression models both revealed peritumoral PD-L1 as an independent prognostic factor for OS (HR = 2.853, P = .002) and DFS (HR = 2.362, P = .003). The prognostic value of PD-L1 positivity was validated in the independent data set. CONCLUSIONS: Our data suggest PD-L1 expression in peritumoral hepatocytes is an independent prognostic factor for OS and DFS. This implies that future anti-cancer therapy should target not only residual tumor cells but also the “soil” for promoting tumor growth. Peritumoral PD-L1 could be a good target for adjuvant therapy after hepatectomy.

PD-L1 and PD-L2 expression in the tumor microenvironment including peritumoral tissue in primary central nervous system lymphoma

“…The presence of PD-L1-positive monocytes in the peritumoral stroma was shown to be an independent prognostic factor of overall survival (OS) in hepatocellular carcinoma (HCC) [20]. Another study of HCC reported that the peritumoral PD-L1 expression in hepatocytes is an independent prognostic factor for survival [21]. Therefore, the expression of checkpoint biomarkers in peritumoral tissue as part of the tumor microenvironment should also be investigated to determine their potential role in the tumor immune escape mechanism.…”

Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Opportunities and Challenges

“…PD‐L1 expression in peritumoral hepatocytes is also an independent prognostic factor for OS and disease‐free survival (DFS). Dai et al suggested that future anticancer therapy should target not only residual tumor cells but also the “soil” promoting tumor growth. The levels of circulating PD‐L1 might also be of prognostic value in patients with HCC.…”

Clinicopathologic Significance and Prognostic Value of Programmed Cell Death Ligand 1 (PD-L1) in Patients With Hepatocellular Carcinoma: A Meta-Analysis

“…PD-L1 overexpression may reflect the presence of endogenous host immune response to tumor and serve as a biomarker for predicting survival benefits from adjuvant CIK cell immunotherapy in HCC patients ( 16 ). And peritumoral PD-L1 expression was associated with significantly worse survival compared to the negative expression group ( 17 ). However, the results of some studies are reversed.…”