Co-expression of PD1 and PD-L1 in the tumor cell area, by immune cells, suggests a prognostic role for overall survival in hepatocellular carcinoma

Previous studies have shown that the programmed cell death protein 1 (PD1)/programmed cell death protein ligand 1 (PD-L1) axis regulates immune responses by modulating T-cell activity and maintaining self-tolerance, including in hepatocellular carcinoma (HCC), which is a leading cause of cancer-related mortality worldwide. Within the tumor-immune microenvironment, the PD1/PD-L1 axis influences tumor initiation, progression, and response to therapy. Immune checkpoint inhibitors are improving HCC treatments in a limited number of patients. Biomarker-based stratification of patients for optimal response to therapy is an unmet need. In this study, we explored a possible role for the PD1/PD-L1 pathway in HCC using a tissue microarray (TMA) with paired samples of non-diseased liver tissue, cirrhotic liver tissue, and HCC from 233 donors. Using double immuno-labeling, the spatial distribution of PD1 positive- and PD-L1 positive cells was visualized, and the presence of PD1/PD-L1 double labeled cells was evaluated. These data were correlated to clinical data and morphologic characteristics, as Edmondson-Steiner histological grading. Our data seem to indicate that elevated levels of PD1 in immune cells within the tumor cell area are associated with high Edmondson grading. Multivariate overall survival analyses indicated an independent negative prognostic impact of both the rarely observed PD1/PD-L1 co-expression (HR = 1.63, p = 0.002) and the Edmondson-Steiner grade (HR = 3.31, p = 0.007). Cases with co-expression of PD1 and PD-L1 by immune cells in the tumor cell area seemed to show the worst prognosis, independent of histological Edmondson-Steiner grading. Patients bearing such tumors could be the ones to benefit most from immune treatments. Additional and larger-scale prospective studies are imperative to advance personalized and effective treatment strategies for HCC.