Foxp3 expression in melanoma cells as a possible mechanism of resistance to immune destruction
Foxp3 expression in melanoma cells as a possible mechanism of resistance to immune destruction
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DOI：
10.1007/s00262-011-1025-3
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发表时间：
2011-08-01
影响因子：
5.8
通讯作者：
Gao, Tianwen
中科院分区：
文献类型：
--
作者：
Niu, Junzhou;Jiang, Changli;Gao, Tianwen
叉头转录因子Foxp 3是CD 4（+）CD 25（+）调节性T细胞（TCRs）的唯一决定性标志物，并已被鉴定为TCRs发育和功能的关键调节因子。Foxp 3的表达已被报道在各种实体瘤，包括黑色素瘤。在这项研究中，我们通过对人黑色素瘤组织切片进行免疫组化分析，验证了Foxp 3在肿瘤浸润性TNM和黑色素瘤细胞中的表达。此外，我们通过流式细胞术、共聚焦显微镜分析、逆转录-聚合酶链反应（RT-PCR）和蛋白质印迹法评估了Foxp 3在黑色素瘤细胞系中的表达。使用小干扰RNA（siRNA）抑制黑素瘤细胞中Foxp 3的表达导致B7-H1和转化生长因子（TGF）-β表达下调;相反，Foxp 3过表达导致这些蛋白表达上调。表达Foxp 3的黑素瘤细胞与初始CD 4（+）CD 25（-）T细胞的共培养导致T细胞增殖的强烈抑制。这种抗增殖作用被特异性抑制Foxp 3表达部分消除，并通过过表达Foxp 3有效增强。我们观察到一个衰减的抗增殖作用，甚至当黑色素瘤细胞和T细胞的共培养分离使用Transwell插入。这些发现表明，黑色素瘤细胞可能对T细胞具有Foxp 3依赖性Treg样抑制作用，并表明黑色素瘤细胞对Treg功能的模拟可能代表了黑色素瘤肿瘤微环境中肿瘤对免疫破坏的抵抗性的可能机制。
The forkhead transcription factor Foxp3 is the only definitive marker of CD4(+)CD25(+) regulatory T cells (Tregs) and has been identified as a key regulator in the development and function of Tregs. Foxp3 expression has been reported in a variety of solid tumors, including melanoma. In this study, we validated Foxp3 expression in both tumor-infiltrating Tregs and melanoma cells by performing immunohistochemical analysis of human melanoma tissue sections. Further, we assessed Foxp3 expression in melanoma cell lines by performing flow cytometry, confocal microscopic analysis, reverse transcription-polymerase chain reaction (RT-PCR), and Western blotting. Inhibition of Foxp3 expression in melanoma cells using small interfering RNA (siRNA) resulted in downregulation of B7-H1 and transforming growth factor (TGF)-beta expression; in contrast, Foxp3 overexpression resulted in the upregulation of the expression of these proteins. Coculture of Foxp3-expressing melanoma cells with naive CD4(+)CD25(-) T cells resulted in strong inhibition of T-cell proliferation. This antiproliferative effect was partially abrogated by specific inhibition of Foxp3 expression and was effectively enhanced by overexpression of Foxp3. We observed an attenuated antiproliferative effect even when melanoma cells and T cells in the coculture were separated using Transwell inserts. These findings indicated that melanoma cells could have Foxp3-dependent Treg-like suppressive effects on T cells and suggested that the mimicking of Treg function by melanoma cells may represent a possible mechanism of tumor resistance to immune destruction in the melanoma tumor microenvironment.