Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects.
Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects.
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DOI：
10.1172/jci21102
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发表时间：
2004-08
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通讯作者：
C. Borg;M. Terme;J. Taïeb;C. Ménard;C. Flament;C. Robert;K. Maruyama;H. Wakasugi;E. Angevin;K. Thielemans;A. Le Cesne;Veronique Chung-Scott;V. Lazar;I. Tchou;F. Crépineau;F. Lemoine;J. Bernard;J. Fletcher;A. Turhan;J. Blay;A. Spatz;J. Emile;M. Heinrich;S. Mécheri;T. Tursz;L. Zitvogel
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作者：
C. Borg;M. Terme;J. Taïeb;C. Ménard;C. Flament;C. Robert;K. Maruyama;H. Wakasugi;E. Angevin;K. Thielemans;A. Le Cesne;Veronique Chung-Scott;V. Lazar;I. Tchou;F. Crépineau;F. Lemoine;J. Bernard;J. Fletcher;A. Turhan;J. Blay;A. Spatz;J. Emile;M. Heinrich;S. Mécheri;T. Tursz;L. Zitvogel
胃肠道间质瘤（GIST）表达的KIT或PDGF受体的突变亚型被认为是STI 571（甲磺酸伊马替尼;格列卫）的治疗靶点，STI 571是这些酪氨酸激酶受体的特异性抑制剂。Gleevec在缺乏典型受体突变的GIST中的临床疗效的病例报告促使人们寻找替代的作用模式。在这里，我们表明，格列卫可以作用于宿主树突状细胞，促进NK细胞活化。DC介导的NK细胞活化在体外和体内通过用Gleevec处理DC以及通过KIT的功能丧失突变来触发。因此，在体外对格列卫的抗增殖作用无效的肿瘤在体内以NK细胞依赖性方式对格列卫产生反应。GIST患者接受格列卫治疗的纵向研究显示，治疗诱导的NK细胞IFN-γ产生增加，与增强的抗肿瘤反应相关。这些数据指出了格列卫抗肿瘤作用的新模式。
Mutant isoforms of the KIT or PDGF receptors expressed by gastrointestinal stromal tumors (GISTs) are considered the therapeutic targets for STI571 (imatinib mesylate; Gleevec), a specific inhibitor of these tyrosine kinase receptors. Case reports of clinical efficacy of Gleevec in GISTs lacking the typical receptor mutations prompted a search for an alternate mode of action. Here we show that Gleevec can act on host DCs to promote NK cell activation. DC-mediated NK cell activation was triggered in vitro and in vivo by treatment of DCs with Gleevec as well as by a loss-of-function mutation of KIT. Therefore, tumors that are refractory to the antiproliferative effects of Gleevec in vitro responded to Gleevec in vivo in an NK cell-dependent manner. Longitudinal studies of Gleevec-treated GIST patients revealed a therapy-induced increase in IFN-gamma production by NK cells, correlating with an enhanced antitumor response. These data point to a novel mode of antitumor action for Gleevec.