Abstract
BACKGROUND AND PURPOSE: Few detailed studies about the correlations among the expanded prevalence, elevated function of Treg cells in tumor microenvironment of hepatocellular carcinoma (HCC), and different clinical tumor stage were reported. The purpose of the present study was to examine the presence and functions of CD4(+)CD25(high) regulatory T cell (Treg cell) in tumor microenvironment from early and late stages and reveal the potential underlying mechanisms that may be responsible. METHOD: The prevalence of Treg in peripheral blood and fresh tissue samples from 31 patients with HCC after radical hepatectomy and 9 controls was detected. CD127 was selected as a Treg cell maker to test the cell populations and compared its expressions with ICOS. The expressions of FOXP3 mRNA were analyzed. The migration, proliferation, and suppression functions of Treg cell were observed. IFN-γ., IL-10, TGF-ß, CCL-17, CCL-22, and SDF-1 in cell supernatant were detected. Among all of the tests, the relations among the different TNM tumor stages, populations, and functions of Treg cells were evaluated. RESULTS: The prevalence of Treg cell was significantly higher in the peripheral blood and in tumor tissue compared with those in normal donors. Increased numbers of Treg cell were showed in peripheral blood as well as in tumor tissue. High levels of IL-10 and TGF-ß, but little IFN-γ, were detected in the tumor microenvironment. Treg cells potently suppressed the functions and proliferation of CD4(+)CD25(-) T cells. High levels of SDF-1 were detected in malignant biopsies compared with those in benign regions, significantly increased in stage III. Plasma from the same patient was able to chemoattract Treg cell but that was lesser extent than those in tumor supernatant. Also, supernatant in advanced stage tumors exhibited powerful chemoattractic activity. SDF-1 played an important role in the recruited functions of Treg cell into tumor microenvironment of early and advanced stages. The expressions of Foxp3 mRNA increased in different TNM stages. The increased prevalence and expanded function of Treg cells in the tumor microenvironment of HCC were correlated with the cancer stage. CONCLUSION: The increase in frequency of Treg cells might play a role in modulation of the immune response against HCC in different TNM stages. The substance secreted in tumor microenvironment recruited CD4(+)CD25(+) Treg cells to tumor sites to contribute to the prosperity and growth of the tumors. The performance of Treg cells in different TNM stages of tumor microenvironment might be acted as the route to evaluate the immunotherapy-based methods, promote therapy effect, and consequently to increase the survival rate in HCC.