Sorafenib reduces hepatic infiltrated regulatory T cells in hepatocellular carcinoma patients by suppressing TGF-beta signal

J Surg Oncol. 2013 Mar;107(4):422-7. doi: 10.1002/jso.23227. Epub 2012 Jul 25.


Background and objectives: Sorafenib has been shown to improve survival rate of hepatocellular carcinoma (HCC) patients significantly. Decline of tumor infiltrated regulatory T cells (TITs) may account for the activity of sorafenib partially. In this study, the underlying mechanism of sorafenib reducing TITs was investigated.

Methods: Tumor infiltrated mononuclear cells (TIMs), which were isolated form 19 HCC patients with or without sorafenib therapy, were analyzed by flow cytometry. TGF-β signal pathways were analyzed by immunoblotting. In vitro test, naïve T cells were induced to regulatory T cells (Tregs) with or without sorafenib. After 3 days of culture, percentage of Tregs from CD4+ cells and TGF-β signal pathways were analyzed. Meanwhile, TIMs from HCC patients without sorafenib treatment were cultured in the presence of sorafenib, and then the percentage of Foxp3 expressing cells from TIMs was analyzed.

Results: TITs were increased in HCC patients compared with controls. However, after sorafenib therapy, TITs were decreased significantly and TGF-β signal pathways were down-regulated. Additionally, in the presence of sorafenib, induction of Tregs was inhibited and TGF-β signal pathways in resulting cells were down-regulated. However, sorafenib treatment did not affect the percentage of Foxp3 expressing cells from TIMs in vitro.

Conclusions: Sorafenib reducing TITs in HCC patients are associated with down-regulation of TGF-β signal. This finding may help us for better understanding the activity of sorafenib in HCC patients.

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacology*
  • Blotting, Western
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / immunology
  • Carcinoma, Hepatocellular / metabolism
  • Down-Regulation
  • Female
  • Flow Cytometry
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Leukocytes, Mononuclear / drug effects*
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / immunology
  • Liver Neoplasms / metabolism
  • Male
  • Middle Aged
  • Niacinamide / administration & dosage
  • Niacinamide / analogs & derivatives*
  • Niacinamide / pharmacology
  • Phenylurea Compounds / administration & dosage
  • Phenylurea Compounds / pharmacology*
  • Protein Kinase Inhibitors / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Sorafenib
  • T-Lymphocytes, Regulatory / drug effects*
  • Transforming Growth Factor beta / antagonists & inhibitors*
  • Transforming Growth Factor beta / metabolism


  • Antineoplastic Agents
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Transforming Growth Factor beta
  • Niacinamide
  • Sorafenib