Bioinformatics mining and clinical validation of CD274 as a prognostic indicator in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a malignant tumour with high global incidence and mortality, featuring limited therapeutic options and poor prognosis, which necessitates novel prognostic biomarkers. The immune checkpoint molecule CD274 (Programmed Death-Ligand 1, PD-L1) correlates with poor prognosis in most solid tumours, yet its prognostic value in HCC remains controversial, and circulating levels are unclear. This study aimed to multi-dimensionally investigate CD274's expression patterns and clinical significance in HCC.

Bioinformatics analyses were performed on The cancer genome atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases to screen differentially expressed genes, with functional and pathway annotations via Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), and Single-Sample Gene Set Enrichment Analysis (ssGSEA). Survival analysis and univariate/multivariate Cox proportional hazards regression models were used to assess the prognostic value of CD274. PD-L1 protein expression was validated by immunohistochemistry (IHC) on HCC tissue microarrays. Serum PD-L1 concentrations were detected by ELISA in treatment-naive HCC patients and healthy controls.

CD274 was lowly expressed in HCC tissues versus normal ones, and its expression correlated with TNF-α/NF-κB, complement, IFN-γ, adipogenesis and oxidative phosphorylation pathways, as well as lymphocyte-mediated immunity, immune globulin complexes and antigen binding. High CD274 expression negatively correlated with Th17 cells but positively with helper T cells, activated dendritic cells (aDCs), Th1 cells, T cells and macrophages via ssGSEA. Patients with high CD274 expression had longer overall survival (OS), disease-specific survival (DSS) and progression-free interval (PFI); multivariate Cox regression confirmed CD274 as an independent protective factor for DSS. PD-L1 protein expression showed no significant difference between HCC and normal liver tissues. Serum PD-L1 median was 349.6 pg/mL in HCC patients, significantly higher than 181.3 pg/mL in healthy controls.

This study first identifies a unique "low tissue expression and elevated peripheral blood level" pattern of CD274 in HCC, with intratumoural high expression correlating with favourable prognosis. CD274 may exert distinct roles in local tumour and systemic immune regulation, and serum CD274 is a promising prognostic biomarker for HCC worthy of further research.