An activated CD8⁺ T cell-based signature stratifies prognosis and suggests differential sensitivity to immune checkpoint inhibitors in hepatocellular carcinoma

Abstract

Aim: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, with heterogeneous responses to immune checkpoint inhibitors (ICIs). Activated CD8⁺ T cell plays pivotal role in antitumor immunity, yet their systematic integration into a prognostic and predictive molecular framework is lacking.

Methods: RNA-seq data from 363 HCC patients in The Cancer Genome Atlas (TCGA) and validation cohorts (GSE76427, GSE14520) were analyzed by single-sample gene set enrichment analysis (ssGSEA). We quantified 28 tumor-infiltrating immune cell subsets and performed consensus clustering based on activated CD8⁺ T cell infiltration. Weighted gene co-expression network analysis (WGCNA) identified a CD8⁺ T cell associated gene module. Cox regression analysis selected 17 hub genes, from which an immune infiltration-based prognostic model was constructed and externally validated. The two risk groups were compared for prognosis, molecular features, and immunotherapy sensitivity using immune, stromal, stemness, and tumor immune dysfunction and exclusion (TIDE) scores.

Results: We determined the proportion of activated CD8⁺ T lymphocytes associated with the coexpression network. Cluster 1 and low-risk groups exhibited higher immune infiltration and better prognosis (P < 0.05) than Cluster 2 and high-risk groups. Indicators of immunotherapy response - including lower mutation frequency, copy-number variations (CNVs), and stemness score, along with higher immune, stromal, and TIDE scores - suggested reduced ICI therapy efficacy in Cluster 1/low-risk groups, whereas the opposite pattern was observed in Cluster 2/high-risk groups.

Conclusion: We established a robust prognostic classifier based on activated CD8⁺ T cell-related genes. This model may aid in identifying HCC patients with poor prognosis who are likely to benefit from immune checkpoint inhibitor therapy.

Keywords

Activated CD8⁺ T cell-related genes / immunotherapy / hepatocellular carcinoma / unsupervised cluster analysis

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