急性髓系白血病 (AML) 是成人最常见的血癌类型之一，存活率较低。 NK 细胞在对抗 AML 中发挥着至关重要的作用，免疫检查点表达的改变可能会损害 NK 细胞对抗 AML 的功能。针对某些检查点可能会恢复此功能。 CD96 是一种抑制性免疫检查点，在 AML 患者的 NK 细胞中表达和作用尚不清楚。在本研究中，我们首先评估了 CD96 的表达，并将 CD96 NK 与初次诊断时 AML 患者的 NK 细胞上的抑制性受体和刺激性受体进行了比较。我们观察到表型功能失调的 NK 细胞上 CD96 表达增加。进一步分析表明，CD96 NK 细胞的 IFN-γ 产量低于 CD96- NK 细胞。阻断 CD96 增强了原代 NK 和脐带血来源的 NK (CB-NK) 细胞对抗白血病细胞的细胞毒性。值得注意的是，初次诊断时 CD96 NK 细胞频率较高的患者表现出较差的临床结果。此外，还发现 TGF-β1 可通过 SMAD3 信号传导增强 NK 细胞上的 CD96 表达。这些研究结果表明，CD96 参与了针对 AML 急变的 NK 功能障碍，并且可能是在对抗 AML 的过程中恢复 NK 细胞功能的潜在靶点。版权所有 © 2024 Elsevier B.V. 保留所有权利。

Acute myeloid leukemia (AML) is one of the most common types of blood cancer in adults and is associated with a poor survival rate. NK cells play a crucial role in combating AML, and alterations in immune checkpoint expression can impair NK cell function against AML. Targeting certain checkpoints may restore this function. CD96, an inhibitory immune checkpoint, has unclear expression and roles on NK cells in AML patients. In this study, we initially evaluated CD96 expression and compared CD96+ NK with the inhibitory receptor and stimulatory receptors on NK cells from AML patients at initial diagnosis. We observed increased CD96 expression on NK cells with dysfunctional phenotype. Further analysis revealed that CD96+ NK cells had lower IFN-γ production than CD96- NK cells. Blocking CD96 enhanced the cytotoxicity of primary NK and cord blood-derived NK (CB-NK) cells against leukemia cells. Notably, patients with a high frequency of CD96+ NK cells at initial diagnosis exhibited poorer clinical outcomes. Additionally, TGF-β1 was found to enhance CD96 expression on NK cells via SMAD3 signaling. These findings suggest that CD96 is invovled in NK dysfunction against AML blast, and might be a potential target for restoring NK cell function in the fight against AML.Copyright © 2024 Elsevier B.V. All rights reserved.