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-B2 (TGF-B2), but not TGF-B1 stimulation in these cells, and was partially suppressed following antibody-mediated neutralization of TGF-B2. The TGF-B2 effect could be mimicked by ectopic expression of a constitutively active TGF-B 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]

Cancer cell-derived IL-1α induces CCL22 and the recruitment of regulatory T cells

“…Nothing is known about the role of the Treg-attracting chemokine CCL22 in these tumors. 36,37 We found that the majority of HCC and all pancreatic cancer samples were infiltrated with CCL22-expressing immune cells. We show here for the first time that tumor cells potently induce CCL22 secretion in leukocytes.…”

An evaluation of the clinical significance of FOXP3+ infiltrating cells in human breast cancer

“…In this study, we observed FOXP3 + cell infiltration in most of the tumours. Recent studies have reported the expression of FOXP3 mRNA and protein in a limited number of pancreatic carcinoma cells, cell lines [54], and other tumour cell lines of several origins, including breast cancer [55].…”

Human FOXP3 and cancer

“…In the first one, FOXP3 expression was restricted to the tumor cells. Normal pancreatic duct cells were devoid of FOXP3 expression, but FOXP3 was detected by immunohistochemistry in human pancreatic cancer cells (Hinz et al, 2007). Cancer cell staining was cytoplasmic in most patients, whereas in others, it was predominantly nuclear.…”

“…A nuclear localization of FOXP3 was also reported for most human normal and cancer cells expressing this factor (Zuo et al, 2007b;Ebert et al, 2008;Wang et al, 2009). However, a predominant cytoplasmic FOXP3 labeling was reported for human pancreatic cancer cells (Hinz et al, 2007). In a recent work dealing with two large series of breast cancer specimens, immunohistological FOXP3 staining was localized predominantly in the tumor cell cytoplasm, whereas a few specimens showed only nuclear staining (Merlo et al, 2009).…”