CD4(+) regulatory T cells in gastric cancer mucosa are proliferating and express high levels of IL-10 but little TGF-β.

BACKGROUND: An increase of regulatory T cells, defined as CD25(high)- and/or FOXP3(+)-expressing CD4(+) T cells, within tumors has been reported in several studies. Tregs promote tumor growth by modulating the antitumor immune response, mainly through inhibition of T-cell-mediated tumor cell killing: this has been suggested to be dependent on IL-10 and/or TGF-β. In stomach cancer, the mechanisms behind the accumulation of Tregs in tumor tissue has not been fully elucidated, and neither has Treg gene expression in situ.

MATERIALS AND METHODS: Stomach tissue from gastric cancer patients undergoing gastric resection was analyzed using flow cytometry and cell sorting, followed by RT-PCR.

RESULTS: We observed that stomach CD4(+) FOXP3(+) T cells proliferated to a higher degree than CD4(+) FOXP3(-) T cells, which may contribute to Treg accumulation in the mucosa. By analyzing DNA methylation, we demonstrated that both proliferating and nonproliferating FOXP3(+) T cells exhibited complete demethylation of the FOXP3 gene, indicating a stable FOXP3 expression in both cell populations. Furthermore, analysis of T-cell populations isolated directly from the tumor and tumor-free mucosa demonstrated that CD4(+) CD25(high) T cells have a higher IL-10/IFN-γ gene expression ratio but express lower levels of TGF-β than CD4(+) CD25(low/-) T cells.

CONCLUSION: We demonstrate strong proliferation among regulatory CD4(+) FOXP3(+) CD25(high) T cells in the gastric cancer mucosa. These local Treg express a suppressive cytokine profile characterized by high IL-10 and low TGF-β and IFN-γ production.