title: Foxp3 expression in pancreatic carcinoma cells as a novel mechanism of immune evasion in cancer.
abstract: 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-beta2 (TGF-beta2), but not TGF-beta1 stimulation in these cells, and was partially suppressed following antibody-mediated neutralization of TGF-beta2. The TGF-beta2 effect could be mimicked by ectopic expression of a constitutively active TGF-beta 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.
authors.affiliation: Division Molecular Oncology, Department for General Surgery, Institute of Immunology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Hinz
authors.forename: Laia
authors.initials: L
authors.lastname: Pagerols-Raluy
authors.forename: Hans-Heinrich
authors.initials: HH
authors.lastname: Oberg
authors.forename: Ole
authors.initials: O
authors.lastname: Ammerpohl
authors.forename: Sandra
authors.initials: S
authors.lastname: Grüssel
authors.forename: Bence
authors.initials: B
authors.lastname: Sipos
authors.forename: Robert
authors.initials: R
authors.lastname: Grützmann
authors.forename: Christian
authors.initials: C
authors.lastname: Pilarsky
authors.forename: Hendrik
authors.initials: H
authors.lastname: Ungefroren
authors.forename: Hans-Detlev
authors.initials: HD
authors.lastname: Saeger
authors.forename: Günter
authors.initials: G
authors.lastname: Klöppel
authors.forename: Dieter
authors.initials: D
authors.lastname: Kabelitz
authors.forename: Holger
authors.initials: H
authors.lastname: Kalthoff
mesh_terms: D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D018920:Coculture Techniques; D051858:Forkhead Transcription Factors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D053781:Transforming Growth Factor beta2 / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D019139:Tumor Escape / Q000235:genetics*