A novel small molecule inhibitor of signal transducers and activators of transcription 3 reverses immune tolerance in malignant glioma patients
A novel small molecule inhibitor of signal transducers and activators of transcription 3 reverses immune tolerance in malignant glioma patients
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DOI：
10.1158/0008-5472.can-07-1243
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发表时间：
2007-10-15
期刊：
影响因子：
11.2
通讯作者：
Heimberger, Amy B.
中科院分区：
文献类型：
--
作者：
Hussain, S. Farzana;Kong, Ling-Yuan;Heimberger, Amy B.
克服实体癌患者中严重的免疫抑制阻碍了有效的免疫疗法。信号转导和转录激活因子3（STAT3）最近已成为有效免疫疗法的一个潜在靶点，在本研究中，我们描述了一种新型的STAT3小分子抑制剂，它能够在小鼠体内穿透中枢神经系统（CNS），在体外以生理相关剂量发挥作用，并逆转从多形性胶质母细胞瘤（GBM）患者中分离出的免疫细胞的耐受性。具体而言，它诱导外周巨噬细胞和肿瘤浸润小胶质细胞上共刺激分子的表达，刺激免疫刺激性细胞因子白细胞介素2（IL - 2）、IL - 4、IL - 12和IL - 15的产生，并诱导对CD3刺激无反应的GBM患者的效应T细胞增殖。我们表明，STAT3抑制后免疫反应的功能增强伴随着几个关键的细胞内信号分子的上调，这些分子对T细胞和单核细胞的激活起着关键的调节作用。具体来说，STAT - 3抑制剂分别增强了单核细胞中Syk（Tyr(352)）和T细胞中ZAP - 70（Tyr(319)）的磷酸化，这与 toll - 样受体和T细胞受体激动剂形成鲜明对比。这种新型的小分子STAT3抑制剂因其能穿透中枢神经系统、易于肠胃外给药、具有直接的肿瘤细胞毒性以及在免疫抑制的癌症患者中能产生强大的免疫辅助反应，在临床应用方面具有巨大潜力。
Overcoming the profound immunosuppression in patients with solid cancers has impeded efficacious immunotherapy. Signal transducers and activators of transcription 3 (STAT3) has recently emerged as a potential target for effective immunotherapy, and in this study, we describe a novel small molecule inhibitor of STAT3 that can penetrate the central nervous system (CNS) in mice and in physiologically relevant doses in vitro and reverse tolerance in immune cells isolated from glioblastoma multiforme (GBM) patients. Specifically, it induces the expression of costimulatory molecules on peripheral macrophages and tumor-infiltrating microglia, stimulates the production of the immune-stimulatory cytokines interleukin 2 (IL-2), IL-4, IL-12, and IL-15, and induces proliferation of effector T cells from GBM patients that are refractory to CD3 stimulation. We show that the functional enhancement of immune responses after STAT3 inhibition is accompanied by up-regulation of several key intracellular signaling molecules that critically regulate T-cell and monocyte activation. Specifically, the phosphorylation of Syk (Tyr(352)) in monocytes and ZAP-70 (Tyr(319)) in T cells are enhanced by the STAT-3 inhibitor in marked contrast to toll-like receptor and T-cell receptor agonists, respectively. This novel small molecule STAT3 inhibitor has tremendous potential for clinical applications with its penetration into the CNS, easy parental administration, direct tumor cytotoxicity, and potent immune adjuvant responses in immunosuppressed cancer patients.