Foxp3 expression in pancreatic carcinoma cells as a novel mechanism of immune evasion in cancer
Foxp3 expression in pancreatic carcinoma cells as a novel mechanism of immune evasion in cancer
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DOI：
10.1158/0008-5472.can-06-3304
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发表时间：
2007-09-01
期刊：
影响因子：
11.2
通讯作者：
Kalthoff, Holger
中科院分区：
文献类型：
--
作者：
Hinz, Sebastian;Pagerols-Raluy, Laia;Kalthoff, Holger
叉头转录因子 Foxp3 在 CD4+CD25+ 调节性 T 细胞 (Treg) 中高度表达，最近被确定为介导其抑制功能的关键角色。在这里，我们首次描述了Foxp3在胰腺导管腺癌细胞和肿瘤中的表达和功能。在这些细胞中，Foxp3 表达是由转化生长因子-β 2 (TGF-β 2) 而非 TGF-β 1 刺激诱导的，并且在抗体介导的 TGF-β 2 中和后部分受到抑制。TGF-β 2 效应可以通过组成型活性 TGF-β I 型受体/ALK5 突变体的异位表达来模拟。在胰腺癌细胞中用小干扰 RNA (siRNA) 下调 Foxp3 导致白细胞介素 6 (IL-6) 和 IL-8 表达上调，这为 Foxp3 在这些上皮细胞中也具有负转录活性提供了证据。表达 Foxp3 的肿瘤细胞与初始 T 细胞共培养完全抑制 T 细胞增殖，但不抑制激活，并且在特异性抑制 Foxp3 表达后，这种抗增殖作用被部分消除。这些发现表明胰腺癌细胞与 Treg 细胞具有相同的生长抑制作用，并表明模仿 Treg 功能可能代表胰腺癌免疫逃避的新机制。
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-beta 2 (TGF-beta 2), but not TGF-beta 1 stimulation in these cells, and was partially suppressed following antibody-mediated neutralization of TGF-beta 2. The TGF-beta 2 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.