增强T细胞和NK细胞功能是对抗癌症的免疫治疗策略。阻断抑制性受体（例如 PD-1 和 CTLA4）的抗体可以增强 T 细胞功能，并已成功治愈某些类型的癌症患者。作为抗体靶向特定抑制性受体的替代方法，人们正在寻找抑制 T 细胞活化负调节因子的小分子药物。一个潜在的药理学靶点是二酰甘油 (DAG) 激酶 (DGK) z，它是一种酶，通过磷酸化 DAG 并将其转化为磷脂酸，充当 DAG 的负调节剂。 DAG 介导的信号传导对于通过其 T 细胞受体激活 T 细胞以及各种激活受体下游的 NK 细胞激活至关重要。因此，DGKδ 缺陷的 T 细胞和 NK 细胞在激活受体结合后表现出增强的功能。此外，使用 DGK 选择性抑制剂 ASP1570 治疗可增强 T 细胞功能。在本研究中，我们试图测试 ASP1570 对 DGK z 的急性抑制是否会增强 NK 细胞功能。我们发现 ASP1570 增强了免疫受体刺激的 NK 细胞中 DAG 介导的信号传导。因此，ASP1570 治疗增强了体外免疫受体激活的 NK 细胞的 IFNγ 产生和脱颗粒以及体内 NK 细胞介导的肿瘤清除。因此，ASP1570 增强了 T 细胞和 NK 细胞的功能，这可能会诱导免疫疗法更持久的抗肿瘤反应。版权所有 © 2023 Elsevier B.V. 保留所有权利。

The enhancement of T cell and NK cell function is an immunotherapeutic strategy for combating cancer. Antibodies that block inhibitory receptors, such as PD-1 and CTLA4, augment T cell function and have been successful in curing patients with some types of cancer. As an alternative approach to targeting specific inhibitory receptors by antibodies, small molecule drugs that inhibit negative regulators of T cell activation have been sought. One potential pharmacological target is diacylglycerol (DAG) kinase (DGK)ζ, which is an enzyme that acts as a negative regulator of DAG by phosphorylating DAG and converting it into phosphatidic acid. DAG-mediated signaling is critical for T cell activation through its T cell receptor and NK cell activation downstream of a variety of activating receptors. Thus, DGKζ-deficient T cells and NK cells display increased function upon activating receptor engagement. Moreover, treatment with the DGKζ-selective inhibitor ASP1570 augments T cell function. In this study, we sought to test whether the acute inhibition of DGKζ by ASP1570 augments NK cell function. We find that ASP1570 enhances DAG-mediated signaling in immunoreceptor-stimulated NK cells. Accordingly, ASP1570 treatment enhanced IFNγ production and degranulation of immunoreceptor-activated NK cells in vitro and NK cell-mediated tumor clearance in vivo. Thus, ASP1570 enhances both T and NK cell function, which could possibly induce more durable anti-tumor responses for immunotherapy.Copyright © 2023 Elsevier B.V. All rights reserved.