Basic Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Nov 15, 2020; 12(11): 1255-1271
Published online Nov 15, 2020. doi: 10.4251/wjgo.v12.i11.1255
Programmed death 1, ligand 1 and 2 correlated genes and their association with mutation, immune infiltration and clinical outcomes of hepatocellular carcinoma
Qiu-Ju Sheng, Wen-Yue Tian, Xiao-Guang Dou, Chong Zhang, Yan-Wei Li, Chao Han, Yao-Xin Fan, Ping-Ping Lai, Yang Ding
Qiu-Ju Sheng, Wen-Yue Tian, Xiao-Guang Dou, Chong Zhang, Yan-Wei Li, Chao Han, Yao-Xin Fan, Ping-Ping Lai, Yang Ding, Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China
Author contributions: Sheng QJ, Tian WY, and Dou XG designed the research study; Sheng QJ, Zhang C, and Ding Y performed the research; Li YW, Han C, and Fan YX contributed new reagents and analytic tools; Shen QJ, Ding Y, and Lai PP analyzed the data and wrote the manuscript; all authors have read and approved the final manuscript.
Supported by National Science and Technology Major Project, No. 2017ZX10201201 and No. 2017ZX10202202; and Liaoning Province Natural Science Foundation, No. 20180550096.
Institutional review board statement: This research did not involve any human or animal experiments.
Conflict-of-interest statement: All of the authors declare that there is no conflict of interest to disclose.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Yang Ding, PhD, Professor, Department of Infectious Diseases, Shengjing Hospital of China Medical University, No. 39 Huaxiang Road, Tiexi District, Shenyang 110022, Liaoning Province, China. yding0903@sina.com
Received: June 12, 2020
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
Processing time: 153 Days and 1.9 Hours
ARTICLE HIGHLIGHTS
Research background

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). 

Research motivation

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.

Research objectives

The aim of the study was to explore the possible mechanism of function of PD-1, PD-L1, and PD-L2 in HCC.

Research methods

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. 

Research results

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.

Research conclusions

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.

Research perspectives

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.