Borg Christophe, Terme Magali, Taïeb Julien, Ménard Cédric, Flament Caroline, Robert Caroline, Maruyama Koji, Wakasugi Hiro, Angevin Eric, Thielemans Kris, Le Cesne Axel, Chung-Scott Véronique, Lazar Vladimir, Tchou Isabelle, Crépineau Florent, Lemoine François, Bernard Jacky, Fletcher Jonhantan A, Turhan Ali, Blay Jean-Yves, Spatz Alain, Emile Jean-François, Heinrich Michael C, Mécheri Salah, Tursz Thomas, Zitvogel Laurence
Department of Clinical Biology, Equipe de Recherche Mixte 0208, INSERM, Institut Gustave Roussy, Villejuif, France.
J Clin Invest. 2004 Aug;114(3):379-88. doi: 10.1172/JCI21102.
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.
胃肠道间质瘤（GISTs）所表达的KIT或血小板衍生生长因子（PDGF）受体的突变亚型被认为是STI571（甲磺酸伊马替尼；格列卫）的治疗靶点，STI571是这些酪氨酸激酶受体的特异性抑制剂。格列卫对缺乏典型受体突变的GISTs具有临床疗效的病例报告促使人们寻找另一种作用方式。在此我们表明，格列卫可作用于宿主树突状细胞（DCs）以促进自然杀伤细胞（NK细胞）的激活。体外和体内实验均显示，用格列卫处理DCs以及KIT功能丧失性突变均可触发DC介导的NK细胞激活。因此，体外对格列卫抗增殖作用具有抗性的肿瘤在体内对格列卫的反应呈NK细胞依赖性。对接受格列卫治疗的GIST患者的纵向研究显示，治疗可诱导NK细胞产生γ干扰素增加，这与增强的抗肿瘤反应相关。这些数据表明格列卫具有一种新的抗肿瘤作用模式。
