CXCL5/CXCL8 is a promising potential prognostic and tumor microenvironment-related cluster in hepatocellular carcinoma

Background:Immune checkpoint blockers (ICBs) are increasingly applied to treat patients with advanced HCC. However, the overall survival (OS) of HCC patients is still unsatisfactory, and there is no confirmed immune-related and prognostic gene to identify patients who could clinically benefit from this treatment. The tumor microenvironment (TME) is known to be closely related to immunotherapy and plays a pivotal role in the recurrence and progression of HCC. Our aim is to explore TME-related genes and identify the prognostic value in HCC patients. Methods: ESTIMATE, immune, and stromal scores were calculated for HCC patients based on RNA expression data from The Cancer Genome Atlas database. Differential expression analysis was performed to screen the differentially expressed genes (DEGs). A protein-protein interaction (PPI) network was constructed to identify the key DEGs. Univariate and multivariate Cox analyses were adopted to validate hub DEGs associated with clinical prognosis, and a single-sample gene set enrichment analysis (ssGSEA) algorithm was used to dissect the landscape of tumor-infiltrating cells (TIC) in HCC. Finally, the relationship between hub immune-related genes and TIC was explored through difference and correlation analyses. Results: ESTIMATE, immune and stromal scores were all found to be associated with the OS of patients (P<0.05). A total of 1,112 DEGs were identified by comparing low and high score groups of immune and stromal scores. Most of DEGs were enriched in immune-related gene sets by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Additionally, the top 34 genes were included in the protein-protein interaction (PPI) network, and univariate Cox analysis focus on a novel prognosisrelated gene cluster CXCL.5/CXCL.8 (P<0.001). Regarding the immune landscape of HCC, univariable Cox regression analysis showed six immune cells to be associated with OS. Finally, 21 immune cells were commonly determined between high and low expression of CXCL5/CXCL8, suggesting there is a close relationship between expression of CXCL5 and CXCL8. Conclusions: Our study has revealed that the immune-related gene cluster of CXCL5 /CXCL8 could be a promising prognostic indicator for HCC and a potential novel biomarker to guide the selection of HCC patients for ICB immunotherapy.