title: Increase of CD4+ CD25+ regulatory T-cells in the liver of patients with hepatocellular carcinoma.
abstract: OBJECTIVE
  The immune response to tumor-specific antigens is typically unable to control the growth and spread of malignant cells. Accumulating evidence indicates that the suppressive effects of CD4+ CD25+ regulatory T-cells are at least partially responsible for the failure of immune-mediated elimination of tumor cells.
  
  
  METHODS
  We have studied 25 patients with hepatocellular carcinoma (HCC). The liver tissues with HCC were separated into the marginal region of tumor (peri-tumor region) and the non-tumor region distant from the tumor. CD4+ CD25+ T-cells were quantified in the blood and the liver by flow cytometry and immunohistochemistry, and their effect on T-cell proliferation and activation was determined.
  
  
  RESULTS
  We found a significant increase in both the proportion and absolute numbers of CD4+ CD25+ T-cells in the peri-tumor regions, but not in unaffected areas (9.5 +/- 4.5 vs. 4.6 +/- 2.8%, P = 0.011). CD4+ CD25+ T-cells isolated from peri-tumor regions displayed phenotype markers characteristic of regulatory T-cells, and expressed Foxp3 mRNA. CD8+ T-cells in peri-tumor regions were inversely proportional to CD4+ CD25+ T-cells in the same region (P < 0.001). Moreover, isolated CD4+ CD25+ T-cells inhibited autologous CD8+ T-cell proliferation.
  
  
  CONCLUSIONS
  Our results suggest that CD4+ CD25+ T-cells in the marginal region of HCC may play a critical role in controlling CD8+ cytotoxic T-cell activity and, thereby, contribute to the progression of HCC.
authors.affiliation: Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Xiu Hua
authors.initials: XH
authors.lastname: Yang
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamagiwa
authors.forename: Takafumi
authors.initials: T
authors.lastname: Ichida
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Matsuda
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sugahara
authors.forename: Hisami
authors.initials: H
authors.lastname: Watanabe
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Sato
authors.forename: Toru
authors.initials: T
authors.lastname: Abo
authors.forename: David A
authors.initials: DA
authors.lastname: Horwitz
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Aoyagi
mesh_terms: D000328:Adult; D000368:Aged; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D008113:Liver Neoplasms / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012334:RNA, Neoplasm / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D012334:RNA, Neoplasm