Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Immunology Programme, Centre for Life Sciences, Life Sciences Institute, National University of Singapore, Singapore, Singapore.
Front Immunol. 2019 Jul 25;10:1718. doi: 10.3389/fimmu.2019.01718. eCollection 2019.
T cell activation is mediated by signaling pathways originating from the T cell receptor (TCR). Propagation of signals downstream of the TCR involves a cascade of numerous kinases, some of which have yet to be identified. Through a screening strategy that we have previously introduced, PHA-767491, an inhibitor of the kinases Cdc7 and Cdk9, was identified to impede TCR signaling. PHA-767491 suppressed several T cell activation phenomena, including the expression of activation markers, proliferation, and effector functions. We also observed a defect in TCR signaling pathways upon PHA-767491 treatment. Inhibition of Cdc7/Cdk9 impairs T cell responses, which could potentially be detrimental for the immune response to tumors, and also compromises the ability to resist infections. The Cdc7/Cdk9 inhibitor is a strong candidate as a cancer therapeutic, but its effect on the immune system poses a problem for clinical applications.
T 细胞的激活是由 T 细胞受体（TCR）引发的信号通路介导的。TCR 下游信号的传递涉及一系列的激酶，其中一些激酶尚未被确定。通过我们之前介绍的筛选策略，PHA-767491，一种 Cdc7 和 Cdk9 激酶的抑制剂，被鉴定为可阻碍 TCR 信号。PHA-767491 抑制了几种 T 细胞激活现象，包括激活标记物的表达、增殖和效应功能。我们还观察到 PHA-767491 处理后 TCR 信号通路出现缺陷。Cdc7/Cdk9 的抑制会损害 T 细胞的反应，这可能对肿瘤的免疫反应有害，也会损害抵抗感染的能力。Cdc7/Cdk9 抑制剂是一种很有前途的癌症治疗药物，但它对免疫系统的影响给临床应用带来了问题。
