Programmed death 1, ligand 1 and 2 correlated genes and their association with mutation, immune infiltration and clinical outcomes of hepatocellular carcinoma

BACKGROUND: The exact regulation network of programmed death 1 (PD-1), programmed death ligand 1 (PD-L1), and programmed death ligand 2 (PD-L2) signaling in immune escape is largely unknown. We aimed to describe the gene expression profiles related to PD-1 as well as its ligands PD-L1 and PD-L2, thus deciphering their possible biological processes in hepatocellular carcinoma (HCC). AIM: To find the possible mechanism of function of PD-1, PD-L1, and PD-L2 in HCC. METHODS: Based on the expression data of HCC from The Cancer Genome Atlas, the PD-1/PD-L1/PD-L2 related genes were screened by weighted correlation network analysis method and the biological processes of certain genes were enriched. Relation of PD1/PD-L1/PD-L2 with immune infiltration and checkpoints was investigated by co-expression analysis. The roles of PD-1/PD-L1/PD-L2 in determination of clinical outcome were also analyzed. RESULTS: Mutations of calcium voltage-gated channel subunit alpha1 E, catenin beta 1, ryanodine receptor 2, tumor suppressor protein p53, and Titin altered PD-1/PD-L1/PD-L2 expression profiles in HCC. PD-1, PD-L1, and PD-L2 related genes were mainly enriched in biological procedures of T cell activation, cell adhesion, and other important lymphocyte effects. In addition, PD-1/PD-L1/PD-L2 was related with immune infiltration of CD8 T cells, cytotoxic lymphocytes, fibroblasts, and myeloid dendritic cells. Immune checkpoints of CTLA4, CD27, CD80, CD86, and CD28 were significantly related to the PD-1/PD-L1/PD-L2 axis. Clinically, PD-1 and PD-L2 expression was correlated with recurrence (P = 0.005 for both), but there was no significant correlation between their expression and HCC patient survival. CONCLUSION: Mutations of key genes influence PD-1, PD-L1, and PD-L2 expression. PD-1, PD-L1, and PD-L2 related genes participate in T cell activation, cell adhesion, and other important lymphocyte effects. The finding that PD-1/PD-L1/PD-L2 is related to immune infiltration and other immune checkpoints would expand our understanding of promising anti-PD-1 immunotherapy.