Die Expression von Foxp3 in Pankreascarzinomzelllinien wird durch TGF-β2 funktionell reguliert und vermittelt einen anti-proliferativen Effekt auf naïve T-Zellen

Abstract

Foxp3 is a member of the forkhead/ winged helix transcription factor family which is highly expressed in CD4+CD25+ regulatory T cells and was recently identified as a key player in T cells with regulatory potential. We describe the expression and function of Foxp3 in pancreatic ductal adenocarcinoma cell lines and cancer tissue resulting in an inhibition of proliferation of naive T cells. The expression of Foxp3 in pancreatic cancer cell lines is regulated by TGF-β2 which resembles the mechanisms in regulatory T cells. We detected Foxp3 mRNA and protein expression in different pancreatic cancer cell lines. In 25/39 pancreatic cancer tissues Foxp3 expression was detectable with immunohistochemistry in the tumor cells, but we found no correlation between Foxp3 expression in the tumor cells and tumor stage and overall-survival. In all pancreatic cancer cell lines Foxp3 positive, tumorinfiltrating lymphocytes were detected. Treatment of pancreatic cancer cell lines with TGF-β2 but not TGF-β1 led to an up regulation of Foxp3 mRNA and protein expression. In line with these findings we found that anti-TGF-β2 treatment resulted in Foxp3 down regulation. In co-culture assays of Panc89 cells with naive T-cells a strong anti-proliferative effect on the proliferation of naive T-cells was observed. Interestingly, this effect could be partially reverted after inhibition of FoxP3 expression in Panc89 cells, indicating that this suppressive effect is dependent on FoxP3 expression. This demonstrates that regulation of Foxp3 expression in pancreatic cancer cells may be similar to the known pathways in Treg and that pancreatic cancer cells might mimic functions of Treg through Foxp3-dependent suppression of T-cell proliferation.