Hypoxia-related genes and PD-L1 inhibitor resistance in hepatocellular carcinoma.

Abstract

158 Background: PD-L1 inhibitor in combination with anti-angiogenic drug has become the first-line treatment strategy for unresectable hepatocellular carcinoma (HCC). However, PD-L1 inhibitor resistance remains an essential issue in treating HCC. It has been proved in the tumor microenvironment that hypoxia-induced increase in PD-L1 expression makes a significant impact on drug resistance. Methods: Two public datasets of gene expression profiles (GSE 14520 and GSE 41666) from the Gene Expression Omnibus (GEO) database were analyzed using bioinformatics: (1) HCC tumor versus adjacent normal tissue (N = 214) and (2) normoxia versus anoxia of HepG2 cells (N = 6). HCC-signature and hypoxia-related genes were identified as the differentially expressed genes (DEGs). Gene set enrichment analyses (GSEA) were performed on the DEGs. Furthermore, multiple regression analysis on the TCGA-LIHC dataset (N=371) and construction of the protein-protein interaction (PPI) network were performed to investigate potential PD-L1 regulatory genes and hub genes. Results: A total of 52 genes overlapped in HCC-signature and hypoxia-related DEGs. Five genes were identified by GSEA as being concurrently associated with the PD-L1 expression pathways. Multiple regression analysis results showed 14 potential PD-L1 regulatory genes. Ten hub genes were identified in the PPI network. Finally, three genes (DLGAP5, KIF20A, and TPX2) were found in common and may be regulatory genes affecting PD-L1 expression. Conclusions: In conclusion, our study provides new insights into the potential hypoxia-related mechanisms of PD-L1 inhibitor resistance and contributes to exploring new therapeutic strategies for treating unresectable HCC.