Wang Wenjun, Edington Howard D, Rao Uma N M, Jukic Drazen M, Land Stephanie R, Ferrone Soldano, Kirkwood John M
Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh, Melanoma and Skin Cancer Program, University of Pittsburgh Cancer Institute. Pittsburgh, PA, USA.
Clin Cancer Res. 2007 Mar 1;13(5):1523-31. doi: 10.1158/1078-0432.CCR-06-1387.
The Janus-activated kinase/signal transducers and activators of transcription (STAT) pathway of IFN signaling is important to immunoregulation and tumor progression. STAT1 plays a prominent role in the effector immune response, whereas STAT3 is implicated in tumor progression and down-regulation of the response to type I IFNs. The goal of this study was to understand the effects of high-dose IFNalpha2b (HDI) in relation to the balance of pSTAT1 and pSTAT3.
We evaluated STAT1 and STAT3 jointly as mediators of IFNalpha effects in the setting of a prospective neoadjuvant trial of HDI, in which tissue samples were obtained before and after 20 doses of HDI therapy. Double immunohistochemistry for pSTAT1 and pSTAT3 was done on paired fixed (9 patients) or frozen (12 patients) biopsies.
HDI was found to up-regulate pSTAT1, whereas it down-regulates pSTAT3 and total STAT3 levels in both tumor cells and lymphocytes. Higher pSTAT1/pSTAT3 ratios in tumor cells pretreatment were associated with longer overall survival (P = 0.032). The pSTAT1/pSTAT3 ratios were augmented by HDI both in melanoma cells (P = 0.005) and in lymphocytes (P = 0.022). Of the immunologic mediators and markers tested, TAP2 was augmented by HDI (but not TAP1 and MHC class I/II).
IFNalpha2b significantly modulates the balance of STAT1/STAT3 in tumor cells and host lymphocytes, leading to up-regulation of TAP2 and augmented host antitumor response. The pSTAT1/pSTAT3 ratio in tumor cells at baseline may serve as a useful predictor of clinical outcome in cutaneous melanoma; the modulation of this ratio may serve as a predictor of therapeutic effect.
干扰素信号转导的Janus激酶/信号转导子和转录激活子（STAT）途径对免疫调节和肿瘤进展很重要。STAT1在效应器免疫反应中起重要作用，而STAT3与肿瘤进展及I型干扰素反应的下调有关。本研究的目的是了解高剂量干扰素α2b（HDI）对pSTAT1和pSTAT3平衡的影响。
在一项HDI前瞻性新辅助试验中，我们联合评估STAT1和STAT3作为干扰素α效应的介质，在该试验中，在20剂HDI治疗前后获取组织样本。对配对的固定（9例患者）或冷冻（12例患者）活检组织进行pSTAT1和pSTAT3的双重免疫组化。
发现HDI上调pSTAT1，而下调肿瘤细胞和淋巴细胞中的pSTAT3及总STAT3水平。肿瘤细胞预处理时较高的pSTAT1/pSTAT3比值与更长的总生存期相关（P = 0.032）。HDI在黑色素瘤细胞（P = 0.005）和淋巴细胞（P = 0.022）中均增加了pSTAT1/pSTAT3比值。在测试的免疫介质和标志物中，HDI增加了TAP2（但未增加TAP1和MHC I/II类）。
干扰素α2b显著调节肿瘤细胞和宿主淋巴细胞中STAT1/STAT3的平衡，导致TAP2上调和宿主抗肿瘤反应增强。基线时肿瘤细胞中的pSTAT1/pSTAT3比值可能作为皮肤黑色素瘤临床结局的有用预测指标；该比值的调节可能作为治疗效果的预测指标。
