Bioinformatics Identification of Regulatory Genes and Mechanism Related to Hypoxia-Induced PD-L1 Inhibitor Resistance in Hepatocellular Carcinoma

Int J Mol Sci. 2023 May 13;24(10):8720. doi: 10.3390/ijms24108720.

Abstract

The combination of a PD-L1 inhibitor and an anti-angiogenic agent has become the new reference standard in the first-line treatment of non-excisable hepatocellular carcinoma (HCC) due to the survival advantage, but its objective response rate remains low at 36%. Evidence shows that PD-L1 inhibitor resistance is attributed to hypoxic tumor microenvironment. In this study, we performed bioinformatics analysis to identify genes and the underlying mechanisms that improve the efficacy of PD-L1 inhibition. Two public datasets of gene expression profiles, (1) HCC tumor versus adjacent normal tissue (N = 214) and (2) normoxia versus anoxia of HepG2 cells (N = 6), were collected from Gene Expression Omnibus (GEO) database. We identified HCC-signature and hypoxia-related genes, using differential expression analysis, and their 52 overlapping genes. Of these 52 genes, 14 PD-L1 regulator genes were further identified through the multiple regression analysis of TCGA-LIHC dataset (N = 371), and 10 hub genes were indicated in the protein-protein interaction (PPI) network. It was found that POLE2, GABARAPL1, PIK3R1, NDC80, and TPX2 play critical roles in the response and overall survival in cancer patients under PD-L1 inhibitor treatment. Our study provides new insights and potential biomarkers to enhance the immunotherapeutic role of PD-L1 inhibitors in HCC, which can help in exploring new therapeutic strategies.

Keywords: PD-L1 inhibitor; bioinformatics analysis; combined treatment; drug resistance; hepatocellular carcinoma; hypoxia; immune escape; molecular target.

MeSH terms

  • B7-H1 Antigen / metabolism
  • Carcinoma, Hepatocellular* / drug therapy
  • Carcinoma, Hepatocellular* / genetics
  • Carcinoma, Hepatocellular* / metabolism
  • Computational Biology
  • Genes, Regulator
  • Humans
  • Hypoxia / genetics
  • Immune Checkpoint Inhibitors
  • Liver Neoplasms* / drug therapy
  • Liver Neoplasms* / genetics
  • Liver Neoplasms* / metabolism
  • Tumor Microenvironment / genetics

Substances

  • Immune Checkpoint Inhibitors
  • B7-H1 Antigen

Grants and funding

The APC was funded by Faculty of Health and Social Sciences, Hong Kong Polytechnic University.