Integrative RNA-Sequencing Analysis Reveals T-Cell Exhaustion Signatures and Immune Cell Infiltration in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy associated with significant mortality globally. T-cell exhaustion (TEX) denotes a dysfunctional cellular state involved in persistent antigen exposure or inflammation during chronic infections and cancer. This study aimed to establish a TEX signature which has a predictive value on the outcomes and immune cell infiltration in HCC. TEX genes were identified with the RNA sequencing dataset from a publicly database. A prognostic TEX signature was established in the TCGA cohort by LASSO method, and verified in the GSE76427. The association of hub genes expression and immune cell infiltration, survival outcomes, and drug sensitivity were analyzed using different databases. The expressed status of hub genes was verified based on TCGA and Human Protein Atlas (HPA) database. A TEX-related gene group comprised of six genes (ZNF521, ZEB1, P2RY8, LOX, RBM10, and NFKBIE) was developed for prognosis prediction in HCC. Functional analysis revealed these TEX genes mainly related to Rap1 signaling, transcriptional misregulation in cancer, pathways in cancer, etc. A nomogram model integrated TEX score and pathologic T was generated for survival rate prediction. More importantly, the TEX gene expression was closely related to the proportion of ten immune cell types. Using the data from TCGA sets, patients in high TEX score subtypes exhibited a worse prognosis and more sensitivity to most candidate compounds. Five hub genes were notably dysregulated in HPA samples. The identified six TEX hub genes might be promising markers for diagnostic and prognostic prediction. TEX signature serves as a predictor for some small molecular compound therapy against HCC.