Dissection of the Effects of JAK and BTK Inhibitors on the Functionality of Healthy and Malignant Lymphocytes
Dissection of the Effects of JAK and BTK Inhibitors on the Functionality of Healthy and Malignant Lymphocytes
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DOI：
10.4049/jimmunol.1900321
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发表时间：
2019-10-15
影响因子：
4.4
通讯作者：
Eldering, Eric
中科院分区：
文献类型：
--
作者：
Hofland, Tom;de Weerdt, Iris;Eldering, Eric
尽管出现了小分子抑制剂，但目前慢性淋巴细胞白血病（CLL）的治疗策略并不能治愈，新的治疗方式的探索仍在继续。来自微环境的促生存信号通常通过JAK信号介导。然而，JAK抑制剂是否在CLL治疗中有用还没有广泛的研究。JAK抑制剂是治疗骨髓纤维化的有价值的药物，在移植物抗宿主病中显示出有希望的结果。然而，JAK抑制与感染风险增加有关，可能是因为对其他免疫细胞的影响，这与用于CLL治疗的其他激酶抑制剂（如BTK抑制剂ibrutinib和PI3Kd抑制剂idelalisib）具有相同的特征。我们比较了JAK1/2抑制剂momelotinib和ruxolitinib， BTK抑制剂ibrutinib和tirabrutinib， PI3Kd抑制剂ideelalisib对恶性CLL细胞的功能影响，以及对健康人T、B和NK淋巴细胞的功能影响。除了预期和众所周知的效果外，我们发现抑制剂之间存在一些有趣的差异。莫米洛替尼而非鲁索利替尼阻断细胞因子诱导的CLL细胞增殖。与ruxolitinib相比，Momelotinib也减少了BCR信号，这表明这些JAK抑制剂实际上具有不同的靶标谱。与替拉替尼相反，伊鲁替尼对T细胞活化有抑制作用，可能是因为ITK抑制。值得注意的是，两种BTK抑制剂在混合淋巴细胞反应中刺激ifn - γ的产生。总的来说，我们的结果表明，针对相同靶点的激酶抑制剂可能对淋巴细胞功能有不同的影响。它们独特的特征可以策略性地用于平衡所需的和不需要的淋巴细胞抑制。
Despite the emergence of small molecule inhibitors, current treatment strategies for chronic lymphocytic leukemia (CLL) are not curative, and the search for new therapeutic modalities continues. Prosurvival signaling derived from the microenvironment is often mediated via JAK signaling. However, whether JAK inhibitors are useful in CLL therapy has not been studied extensively. JAK inhibitors are valuable therapeutic agents in myelofibrosis and show promising results in graft-versus-host-disease. However, JAK inhibition is associated with an increased infection risk, presumably because of the effect on other immune cells, a feature shared with other kinase inhibitors used for CLL treatment, such as the BTK inhibitor ibrutinib and the PI3Kd inhibitor idelalisib. We compared functional effects of the JAK1/2 inhibitors momelotinib and ruxolitinib, the BTK inhibitors ibrutinib and tirabrutinib, and PI3Kd inhibitor idelalisib on malignant CLL cells but also on healthy human T, B, and NK lymphocytes. We found several interesting differences among the inhibitors, apart from expected and well-known effects. Momelotinib but not ruxolitinib blocked cytokine-induced proliferation of CLL cells. Momelotinib also reduced BCR signaling, in contrast to ruxolitinib, indicating that these JAK inhibitors in fact have a distinct target spectrum. In contrast to tirabrutinib, ibrutinib had inhibitory effects on T cell activation, probably because of ITK inhibition. Remarkably, both BTK inhibitors stimulated IFN-gamma production in a mixed lymphocyte reaction. Collectively, our results demonstrate that kinase inhibitors directed at identical targets may have differential effects on lymphocyte function. Their unique profile could be strategically employed to balance desired versus unwanted lymphocyte inhibition.