Published online Nov 15, 2020. doi: 10.4251/wjgo.v12.i11.1255
Peer-review started: June 12, 2020
First decision: July 21, 2020
Revised: August 6, 2020
Accepted: September 25, 2020
Article in press: September 25, 2020
Published online: November 15, 2020
The potential regulating network of programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1)/programmed death ligand 2 (PD-L2) signaling in the immune escape is unclear. We aimed to describe the gene expression profiles related with PD-1 and its ligands PD-L1 and PD-L2 to decipher their possible biological processes in hepatocellular carcinoma (HCC).
Although satisfactory effect of anti-PD-1/PD-L1 therapy has been observed in several types of cancers, the potential complicated interaction network of PD-1/PD-L1/PD-L2 related genes in immune escape and immune surveillance still remains unclear.
The aim of the study was to explore the possible mechanism of function of PD-1, PD-L1, and PD-L2 in HCC.
Based on transcriptional data of HCC from TCGA, PD-1/PD-L1/PD-L2 related genes were screened by weighted correlation network analysis and the biological processes of certain genes were enriched. The relation of PD1/PD-L1/PD-L2 expression with immune infiltration and checkpoints was investigated by co-expression analysis. The role of PD-1/PD-L1/PD-L2 in the determination of clinical outcome was also analyzed.
Mutations of calcium voltage-gated channel subunit alpha1 E (CACNA1E), catenin beta 1 (CTNNB1), ryanodine receptor 2 (RYR2), tumor suppressor protein p53 (TP53), and Titin (TTN) altered PD-1/PD-L1/PD-L2 expression profiles in HCC. PD-1/PD-L1/PD-L2 related genes were mainly enriched in biological processes of T cell activation, cell-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 CTLA4, CD27, CD80, CD86, and CD28 were significantly correlated with 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 PD-1/PD-L1/PD-L2 expression and HCC patient survival.
Mutations of key genes influence PD-1/PD-L1/PD-L2 expression. PD-1/PD-L1/PD-L2 related genes participate in T cell activation, cell-cell adhesion, and other important lymphocyte effects. Correlation of PD-1/PD-L1/PD-L2 with immune infiltration and other immune checkpoints would expand our understanding of promising anti-PD-1 immunotherapy.
Mutations of CACNA1E, CTNNB1, RYR2, TP53, and TTN altered PD-1/PD-L1/PD-L2 expression profiles in HCC. The limitation on the effect of mutations on gene expression is that only statistical differences have been observed so far. We will conduct follow-up research on its detailed mechanism. PD-1/PD-L1/PD-L2 related genes were enriched in biological processes of T cell activation, cell-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 CTLA4, CD27, CD80, CD86, and CD28 were significantly correlated with PD-1/PD-L1/PD-L2 axis. Clinically, PD-1 and PD-L2 expression was correlated with recurrence, but there was no significant correlation between PD-1/PD-L1/PD-L2 and survival of HCC patients.