PD‐1 and PD‐L1 upregulation promotes CD8 + T‐cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients

Programmed death 1 (PD‐1) and its ligand (PD‐L1) play pivotal roles in regulating host immune responses. However, the inhibitory effects of this pathway on the function of cytotoxic CD8 + T lymphocytes, the main effector cells in hepatocellular carcinoma (HCC) patients, are not well defined. In this study, we characterized circulating and intratumor PD‐1/PD‐L1 expression and analyzed their association with disease progression in a cohort of hepatitis B virus‐infected patients, including 56 with HCC, 20 with liver cirrhosis (LC) and 20 healthy controls (HC). The frequency of circulating PD‐1 + CD8 + T cells increased with disease progression from LC to HCC patients versus HC. Furthermore, tumor‐infiltrating effector CD8 + T cells showed a drastic increase in PD‐1 expression. These increases in circulating and intratumor PD‐1 + CD8 + T cells could predict poorer disease progression and postoperative recurrence. Immunohistochemical staining showed that PD‐L1 expressing hepatoma cells and apoptotic infiltrating CD8 + T cells were both enriched in tumor sections. In vitro , CD8 + T cells induced PD‐L1 expression on hepatoma cells in an IFN‐γ–dependent manner, which in turn promoted CD8 + T cells apoptosis, and blocking PD‐L1 reversed this effect. Therefore, this study extends our knowledge of the role of the PD‐1/PD‐L1 pathway in tumor evasion and provides evidence for a new therapeutic target in HCC patients.