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Foxp3 Expression in Pancreatic Carcinoma Cells as a Novel Mechanism of Immune Evasion in Cancer

¹ Division Molecular Oncology, ² Department for General Surgery and Thoracic Surgery, ³ Institute of Immunology, and ⁴ Department of Pathology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; and ⁵ Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden, Germany

Requests for reprints: Holger Kalthoff, Division Molecular Oncology, Department of General Surgery and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany. Phone: 49-431-597-1938; Fax: 49-431-597-1939; E-mail: hkalthoff{at}email.uni-kiel.de.

The forkhead transcription factor Foxp3 is highly expressed in CD4+CD25+ regulatory T cells (Treg) and was recently identified as a key player in mediating their inhibitory functions. Here, we describe for the first time the expression and function of Foxp3 in pancreatic ductal adenocarcinoma cells and tumors. Foxp3 expression was induced by transforming growth factor-ß2 (TGF-ß2), but not TGF-ß1 stimulation in these cells, and was partially suppressed following antibody-mediated neutralization of TGF-ß2. The TGF-ß2 effect could be mimicked by ectopic expression of a constitutively active TGF-ß type I receptor/ALK5 mutant. Down-regulation of Foxp3 with small interfering RNA (siRNA) in pancreatic carcinoma cells resulted in the up-regulation of interleukin 6 (IL-6) and IL-8 expression, providing evidence for a negative transcriptional activity of Foxp3 also in these epithelial cells. Coculture of Foxp3-expressing tumor cells with naive T cells completely inhibited T-cell proliferation, but not activation, and this antiproliferative effect was partially abrogated following specific inhibition of Foxp3 expression. These findings indicate that pancreatic carcinoma cells share growth-suppressive effects with Treg and suggest that mimicking Treg function may represent a new mechanism of immune evasion in pancreatic cancer. [Cancer Res 2007;67(17):8344–50]

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