Foxp3 expression in pancreatic carcinoma cells as a novel mechanism of immune evasion in cancer.
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.
Hinz
Sebastian
S
Division Molecular Oncology, Department for General Surgery, Institute of Immunology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Pagerols-Raluy
Laia
L
Oberg
Hans-Heinrich
HH
Ammerpohl
Ole
O
Grüssel
Sandra
S
Sipos
Bence
B
Grützmann
Robert
R
Pilarsky
Christian
C
Ungefroren
Hendrik
H
Saeger
Hans-Detlev
HD
Klöppel
Günter
G
Kabelitz
Dieter
D
Kalthoff
Holger
H
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*