Research Paper Volume 13, Issue 14 pp 18620—18644

Interleukin-2 inducible T-cell kinase: a potential prognostic biomarker and tumor microenvironment remodeling indicator for hepatocellular carcinoma

Binhua Pan1,3,4, *, , Modan Yang1,3,4, *, , Xuyong Wei1,4, , Wangyao Li1,3,4, , Kun Wang1,3,4, , Mengfan Yang1,3,4, , Di Lu1,4, , Rui Wang1,4, , Beini Cen1,4, , Xiao Xu1,2,3,4,5, ,

  • 1 Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
  • 2 Zhejiang University Cancer Center, Hangzhou 310058, China
  • 3 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
  • 4 NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
  • 5 Institute of Organ Transplantation, Zhejiang University, Hangzhou 310003, China
* Equal contribution

Received: November 24, 2020       Accepted: June 23, 2021       Published: July 19, 2021
How to Cite

Copyright: © 2021 Pan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Background: The heterogeneous tumor microenvironment (TME) contributes to poor prognosis of hepatocellular carcinoma (HCC). However, determining the modulation of TME during HCC progression remains a challenge.

Methods: Herein, the stromal score and immune score of HCC samples from The Cancer Genome Atlas database were calculated using the ESTIMATE algorithm and differentially expressed genes (DEGs) were obtained. Key DEGs were identified based on a protein-protein interaction network and survival analysis. Immunohistochemistry was carried out using primary samples to evaluate key DEGs expression. The CIBERSORT algorithm was applied to evaluate immune components. Gene Set Enrichment Analysis (GSEA) and correlation analysis were carried out to determine the relationship between key DEGs and tumor-infiltrating immune cells (TICs).

Results: The stromal score, immune score and estimate score correlated significantly with 1-year recurrence-free survival of patients with HCC. Interleukin-2 inducible T-cell kinase (ITK) was identified as the most prognostic DEG for patients with HCC. GSEA revealed that genes in the high ITK subgroup were enriched in inflammatory-immunological terms. CIBERSORT analysis identified nine TIC subsets that correlated with ITK expression.

Conclusion: We identified ITK as a novel indicator for early post-surgery tumor recurrence and microenvironment remodeling in HCC, providing a potential therapeutic target to treat HCC.


AFP: alpha-fetoprotein; APCs: antigen-presenting cells; DCP: Des-Carboxy Prothrombin; DEG: differentially expressed genes; EBV: Epstein-Barr-Virus; GO: Gene ontology; Gp-73: Golgi protein 73; GSEA: Gene Set Enrichment Analysis; HCC: hepatocellular carcinoma; HLA-DRB5: HLA Class II histocompatibility antigen DRβ5; IHC: Immunohistochemistry; ITK: interleukin-2 inducible T-cell kinase; KEGG: Kyoto Encyclopedia of Genes and Genomes; LUAD: lung adenocarcinomas; NK: natural killer; OPN: osteopontin; OS: overall survival; PCA: principal component analysis; PPI: protein-protein interaction; RFS: recurrence-free survival; TAA: Tumor-associated antigen; TCGA: The Cancer Genome Atlas; TCR: T cell receptor; Texs: exhausted T cells; TICs: tumor-infiltrating immune cells; TME: tumor microenvironment; Tregs: regulatory T cells; VEGF: vascular endothelial growth factor; WHO: World Health Organization.