Paradoxical activation of T cells via augmented ERK signaling mediated by a RAF inhibitor.
Paradoxical activation of T cells via augmented ERK signaling mediated by a RAF inhibitor.
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DOI：
10.1158/2326-6066.cir-13-0160
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发表时间：
2014-01
影响因子：
10.1
通讯作者：
Wolchok JD
中科院分区：
文献类型：
--
作者：
Callahan MK;Masters G;Pratilas CA;Ariyan C;Katz J;Kitano S;Russell V;Gordon RA;Vyas S;Yuan J;Gupta A;Wigginton JM;Rosen N;Merghoub T;Jure-Kunkel M;Wolchok JD
RAF抑制剂选择性阻断BRAF突变型黑色素瘤中的ERK信号传导，并定义了一种基因型指导的方法来治疗这种疾病。RAF抑制剂在BRAF野生型肿瘤细胞中具有相反的作用，在那里它们引起ERK信号传导的过度活化。在这里，我们预测，RAF抑制剂可以增强T细胞活化，根据观察，这些药物矛盾激活ERK信号在BRAF野生型细胞。为了验证这一假设，我们评估了RAF抑制剂BMS 908662在体外和体内对T细胞活化和信号传导的影响。我们观察到T细胞活化以浓度依赖性方式增强，并且这种效应与ERK信号传导增加相对应，与该途径的反常活化一致。此外，我们发现BMS 908662与CTLA-4阻断剂的体内组合增强了T细胞扩增，对应于离体可检测的T细胞中ERK信号传导的超活化。最后，在两种可移植肿瘤模型中，与单独的任一种药物相比，该组合显示出上级抗肿瘤活性。这项研究提供了明确的证据表明，RAF抑制剂可以调节T细胞功能，在体外和体内增强T细胞活化。T细胞中ERK信号传导的特异性激活提供了一种机制来解释当RAF抑制剂与CTLA-4阻断剂组合时在临床前模型中观察到的增强的抗肿瘤活性。
RAF inhibitors selectively block ERK signaling in BRAF-mutant melanomas and have defined a genotype-guided approach to care for this disease. RAF inhibitors have the opposite effect in BRAF wild-type tumor cells, where they cause hyperactivation of ERK signaling. Here, we predict that RAF inhibitors can enhance T cell activation, based upon the observation that these agents paradoxically activate ERK signaling in BRAF wild-type cells. To test this hypothesis, we have evaluated the effects of the RAF inhibitor BMS908662 on T cell activation and signaling in vitro and in vivo. We observe that T cell activation is enhanced in a concentration-dependent manner and that this effect corresponds with increased ERK signaling, consistent with paradoxical activation of the pathway. Furthermore, we find that the combination of BMS908662 with CTLA-4 blockade in vivo potentiates T cell expansion, corresponding with hyperactivation of ERK signaling in T cells detectable ex vivo. Lastly, this combination demonstrates superior anti-tumor activity, compared to either agent alone, in two transplantable tumor models. This study provides clear evidence that RAF inhibitors can modulate T cell function by potentiating T cell activation in vitro and in vivo. Paradoxical activation of ERK signaling in T cells offers one mechanism to explain the enhanced antitumor activity seen when RAF inhibitors are combined with CTLA-4 blockade in preclinical models.