Interleukin-2 Inducible T-Cell Kinase: A Potential Prognostic Biomarker and Tumor Microenvironment Remodeling Indicator for Hepatocellular Carcinoma

Abstract

Background: Hepatocellular carcinoma (HCC) is the dominant type of primary liver cancer, which leads to the fourth-ranked common cause of cancer-related death worldwide. The highly heterogeneous tumor microenvironment (TME) contributes to poor prognosis, particularly tumor recurrence of HCC. There is still a great challenge to illuminate the complicated modulation of TME during HCC progression. Methods: In the current study, RNA expression data and clinical-pathological data of HCC patients were downloaded from The Cancer Genome Atlas (TCGA) database. The immune and stromal scores of the samples were calculated using ESTIMATE algorithm and DEGs were obtained by comparison of low- and high-score groups. Intersection of hubgenes in protein-protein interaction (PPI) network and factors correlated with survival from univariate COX regression analysis were applied to screen out the key DEGs. The proportion of tumor-infiltrating immune cells (TICs) and stromal components were evaluated using CIBERSORT algorithm. Further Gene Set Enrichment Analysis (GSEA) and correlation analysis were carried out to elucidate the relation between ITK and TIC composition. Findings: The Immune score and Estimate score were proved to be significantly correlated with long-term recurrence-free survival (RFS) of HCC patients. 197 DEGs were carried out based on the Immune and Stromal scores. Two factors including interleukin-2 inducible T-cell kinase (ITK) and HLA Class II histocompatibility antigen DRB5 (HLA-DRB5) were identified as key DEGs. Further analysis proved that ITK was the most powerful DEG to evaluate the clinical-pathological characteristics and outcomes of HCC patients.The results of GSEA revealed that genes in the high ITK subgroup were enriched in inflammatory-immunological terms. CIBERSORT analysis for the proportion of TICs indicated that activated CD4+ memory T cells, CD8+ T cells, and M1 Macrophages were positively correlated with ITK expression, while plasma cells, resting natural killer (NK) cells, activated dendritic cells, activated NK cells, naive CD4+ T cells and resting mast cells were negatively correlated with ITK expression. Interpretation: Our work identified ITK as a novel indicator for tumor recurrence and microenvironment remodeling in HCC, and provide a potential therapeutic target for HCC treatment. Funding Statement: National ST National Natural Science Funds for Distinguished Young Scholar of China (No. 81625003); Key Program, National Natural Science Foundation of China (No. 81930016); Key Research & Development Plan of Zhejiang Province (No. 2019C03050); Youth Program of National Natural Science Foundation of China (No.81702858); Medical and health science and technology program of Zhejiang Province (No.2018256286) Declaration of Interests: None.