Purpose: Hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer-related deaths, posing a significant threat to people in diverse regions. T-cell exhaustion (Tex) can hinder the efficacy of immunotherapy in patients with HCC, and the transcription factors that regulate Tex in HCC have not yet been fully elucidated.
Patients and Methods: We used the single sample gene set enrichment analysis (ssGSEA) method to define the transcription factor pathway that regulates Tex and employed LASSO regression analysis to establish Tex related genes (TEXRS). To predict differences in immunotherapy efficacy between the two groups, we used the immunophenotype score and submap algorithm. RT-qPCR was used to detect the expression levels of the model genes in 21 pairs of HCC tissues. Finally, we assessed the cell communication strength and identified ligand receptors using the “CellChat” R package.
Results: Nine Tex transcription factors were identified as regulators of the HCC immune microenvironment, with Tex scores affecting patient survival. Patients with a high Tex Risk Score (TEXRS) had significantly worse overall survival compared to patients with low TEXRS. After adjusting for confounding factors, TEXRS remained an independent prognostic factor. Importantly, TEXRS performed well in multiple independent external validation cohorts. Various algorithms have shown that patients in the low-TEXRS group might benefit more from immunotherapy. Finally, RT-qPCR analysis of 21 HCC samples showed that C7, CD5L, and SDS were significantly downregulated in HCC tissues, consistent with the bioinformatics analysis results.
Conclusion: TEXRS proved to be a valuable predictor of immunotherapy and transcatheter arterial chemoembolization efficacy in patients with HCC. This holds promise for enhancing the prognosis and treatment outcomes of patients with HCC.
Keywords: T-cell exhaustion, transcription factors, single-cell RNA sequencing, immune microenvironment, immunotherapy