Characterization of positively regulate T cell proliferation-related genes in hepatocellular cancer to guide clinical therapy

Abstract Objective: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. T cells are very important in the body's anti-tumor process. However, in HCC, T cell exhaustion not only makes it difficult to implement CAR-T therapy, but also reduces the body's anti-tumor ability or even promotes tumor development. Therefore, it is urgent to explore the relationship between positive regulators of T cells proliferation and HCC. Methods: HCC transcriptome and clinical data were collected from TCGA and ICGC databases. Differentially expressed T-cell positive regulators in the TCGA dataset were analyzed using the R software "limma" package. Univariate COX and Least Absolute Value Convergence and Selection Operator (LASSO) regression analysis established a T cell positive regulator prognostic model, and further combined the risk score with clinicopathological features to construct a nomogram. Single-gene enrichment analysis (ssGSEA) was performed using the R software "gva" package to compare the proportion of immune cells between high and low score groups, and gene set variation (GSVA) to identify significantly enriched signaling pathways in high and low score groups. The "pRRophetic" R software package analyzes the susceptibility of patients with high and low scores to chemotherapy. Further, GO and KEGG pathway enrichment analysis was performed on the differential genes in the high and low score groups, and the "cytoHubba" software was used to find the key differential genes in the high and low score groups.Results: A total of 33 positive regulators of T cell proliferation were identified, and 617 HCC patients were included in the analysis. Among them, 23 T cell positive regulators were significantly differentially expressed in HCC (P<0.05). Patients with high scores in the TCGA dataset had poorer prognosis than those with lower scores, and the results were consistent with the validation results in the ICGC dataset (P<0.05). The levels of antigen-presenting cells, major histocompatibility complex-I, chemokine receptors and immune checkpoints in the high-scoring group were significantly increased (P<0.05). The IC50 values of 5-FU, doxorubicin and mitomycin were significantly lower in the high score group (P<0.05). The highly expressed genes in the high score group were mainly enriched in signaling pathways such as RNA degradation, cell cycle, mismatch repair, and DNA replication, and the highly expressed genes in the low score group were mainly enriched in metabolism-related pathways. The top three key differential genes in the high and low risk groups were CDK1, KIF11, and TOP2A. The prognosis of HCC patients with high expression of CDK1 and low expression was significantly worse (P<0.05), and it was related to clinical stage.Conclusion: The positive regulators of T cell proliferation are significantly differentially expressed in HCC, and the overexpression of related genes brings hope for the application of CAR-T therapy in HCC. The prognostic model of T cell positive regulators promotes the understanding of the characteristics of HCC tumor immune microenvironment infiltration and drug sensitivity, and provides a theoretical basis for the clinical treatment of HCC.