Integrated single-cell and transcriptomic analysis of CD8+CD101+TIM3+ T cells in hepatocellular carcinoma: implications for tumor microenvironment and prognostic modeling

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Background: Hepatocellular carcinoma (HCC) ranks as a leading global cause of cancer-related mortality. Our study investigates the functional role between CD8+CD101+TIM3+ T cells (CCT) and CD8+CD101−TIM3+ T cells in HCC, with a focus on their implications for immunotherapy. Methods: We utilized single-cell RNA sequencing (scRNA-seq) to delineate the transcriptional landscapes and intercellular crosstalk of CCT and CD8+CD101−TIM3+ T cells in HCC tissues. Clinical characteristics and scRNA-seq data were curated from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. For the differentially expressed genes (DEGs), Gene Ontology (GO) functional analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway-enrichment were performed. Prognostic model was constructed using univariate Cox and least absolute shrinkage and selection operator (LASSO) Cox regression model, validated through Kaplan-Meier survival curves and receiver operating characteristic (ROC) curves. A corresponding nomogram was also established to predict the prognosis of HCC patients. Results: Our results indicated that T cell re-clustering revealed four functionally distinct subsets: CD8+ T cells, CD8+CD101−TIM3+ T cells, CCT, and CD4+ T cells. Pseudotime trajectory analysis demonstrated that CD8+CD101−TIM3+ T cells progressively differentiated into CCT, a process mediated by MIF-CD74/CXCR4 and SPP1-CD44 signaling axes. Enrichment analysis identified 1,281 CCT-specific genes enriched in mitochondrial electron transport and oxidative phosphorylation pathways. The prognostic model showed strong discriminatory power for overall survival (OS), achieving areas under the curve of 0.825, 0.873, and 0.865 at 1, 3, and 5 years in the training cohort, compared to 0.654, 0.636, and 0.644 in the validation cohort. The developed nomogram effectively predicts OS for HCC patients. Conclusions: Our findings elucidate the functional alterations of CCT and precursor cells within the context of HCC. The novel prognostic framework provides actionable insights for stratifying patients likely to benefit from combinatorial immunotherapy and chemotherapy.

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