Wang Wenjun, Edington Howard D, Rao Uma N M, Jukic Drazen M, Radfar Arash, Wang Hong, Kirkwood John M
Department of Medicine, Division of Hematology/Oncology, Melanoma and Skin Cancer Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213-2584, USA.
Clin Cancer Res. 2008 Dec 15;14(24):8314-20. doi: 10.1158/1078-0432.CCR-08-0705.
Signal transducer and activator of transcription 5 (STAT5) and STAT3 oppose one another in regulation of the reciprocal development of CD4+CD25+FOXP3+ regulatory T cells (Treg) and T helper 17 (Th17). A reduction in STAT3 is associated with up-regulation of Treg, and STAT5 activation promotes Treg differentiation or function while constraining Th17 generation. The effects of IFNalpha on STAT signaling in relation to tumor tissue Treg and Th17 have not been documented in humans beyond the observations that IFNalpha2b down-regulates STAT3.
Following diagnostic biopsy and before definitive surgery, 20 doses of high-dose IFNalpha2b (HDI) were administered to patients with stage IIIB melanoma who gave written informed consent. Lymph node biopsies, in which both total STAT3 and phosphorylated STAT3 were down-regulated by HDI, were probed with STAT5, FOXP3, CD4, and interleukin 17 (IL-17) with immunohistochemistry and/or immunofluorescence techniques.
The percentage of FOXP3+ lymphocytes determined by immunohistochemistry was up-regulated from 3.06 +/- 0.65% to 9.86 +/- 1.27% (n = 13, P = 0.0002), and this observation was confirmed by immunofluorescence evaluation of CD4+FOXP3+ Tregs. HDI induced STAT5 up-regulation (five cases observed) in melanoma cells and lymphocytes but did not induce the generation of IL-17-expressing lymphocytes. Increased STAT5 expression was associated with increased FOXP3 expression among lymphocytes, and STAT5 was constitutively activated among both melanoma cells and lymphocytes.
IFNalpha2b up-regulates STAT5 and down-regulates STAT3, in conjunction with up-regulation of Treg and inhibition of IL-17-expressing lymphocytes in melanoma tissues. These findings suggest that the effects of IFNalpha may be potentiated through interference with the response of Tregs and/or STAT5.
信号转导及转录激活因子5（STAT5）和STAT3在调节CD4+CD25+FOXP3+调节性T细胞（Treg）和辅助性T细胞17（Th17）的相互发育过程中相互拮抗。STAT3的减少与Treg的上调相关，而STAT5的激活促进Treg的分化或功能，同时抑制Th17的产生。除了观察到IFNα2b下调STAT3外，IFNα对肿瘤组织中Treg和Th17的STAT信号传导的影响在人类中尚未有文献记载。
在诊断性活检后和确定性手术前，对20例签署书面知情同意书的IIIB期黑色素瘤患者给予20剂高剂量IFNα2b（HDI）。用免疫组织化学和/或免疫荧光技术对淋巴结活检组织进行检测，其中HDI可下调总STAT3和磷酸化STAT3，检测指标包括STAT5、FOXP3、CD4和白细胞介素17（IL-17）。
通过免疫组织化学测定的FOXP3+淋巴细胞百分比从3.06±0.65%上调至9.86±1.27%（n = 13，P = 0.0002），CD4+FOXP3+ Treg的免疫荧光评估证实了这一观察结果。HDI诱导黑色素瘤细胞和淋巴细胞中STAT5上调（观察到5例），但未诱导表达IL-17的淋巴细胞生成。淋巴细胞中STAT5表达增加与FOXP3表达增加相关，黑色素瘤细胞和淋巴细胞中STAT5均持续激活。
IFNα2b上调STAT5并下调STAT3，同时上调黑色素瘤组织中的Treg并抑制表达IL-17的淋巴细胞。这些发现表明，IFNα的作用可能通过干扰Treg和/或STAT5的反应而增强。
