Increase of CD4+ CD25+ regulatory T-cells in the liver of patients with hepatocellular carcinoma.
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.
Yang
Xiu Hua
XH
Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Yamagiwa
Satoshi
S
Ichida
Takafumi
T
Matsuda
Yasunobu
Y
Sugahara
Satoshi
S
Watanabe
Hisami
H
Sato
Yoshinobu
Y
Abo
Toru
T
Horwitz
David A
DA
Aoyagi
Yutaka
Y
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
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D012334:RNA, Neoplasm