肿瘤细胞治疗研究
英文原题：CRISPR/Cas9 editing of NKG2A improves the efficacy of primary CD33-directed chimeric antigen receptor natural killer cells.
嵌合抗原受体（CAR）修饰的自然杀伤（NK）细胞在体内对急性髓系白血病（AML）表现出抗白血病活性。
体内研究显示，CAR 修饰的自然杀伤（NK）细胞对急性髓系白血病（AML）具有抗白血病活性。然而，人白细胞抗原（HLA）-E 与抑制性受体 NKG2A 的相互作用常会削弱 NK 细胞介导的肿瘤杀伤。本文介绍一种克服 HLA-E–NKG2A 免疫检查点介导的 CAR-NK 细胞抑制的策略。研究者制备了靶向 AML 的 CD33 特异性 CAR-NK 细胞（CAR33），并结合 CRISPR/Cas9 技术破坏编码 NKG2A 的 KLRC1 基因。通过单细胞多组学分析，我们识别出 CAR33-KLRC1 敲除 NK 细胞的激活和成熟相关转录特征；这些特征在细胞接触 AML 细胞后仍得以保持。此外，CAR33-KLRC1 敲除 NK 细胞在体外和体内均显示出对 AML 细胞系及原代白血病细胞的强效杀伤活性。因此，我们认为，缺失 NKG2A 的 CAR-NK 细胞有潜力绕过 AML 中的免疫抑制。
Chimeric antigen receptor (CAR)-modified natural killer (NK) cells show antileukemic activity against acute myeloid leukemia (AML) in vivo. However, NK cell-mediated tumor killing is often impaired by the interaction between human leukocyte antigen (HLA)-E and the inhibitory receptor, NKG2A. Here, we describe a strategy that overcomes CAR-NK cell inhibition mediated by the HLA-E-NKG2A immune checkpoint. We generate CD33-specific, AML-targeted CAR-NK cells (CAR33) combined with CRISPR/Cas9-based gene disruption of the NKG2A-encoding KLRC1 gene. Using single-cell multi-omics analyses, we identified transcriptional features of activation and maturation in CAR33-KLRC1 ko -NK cells, which are preserved following exposure to AML cells. Moreover, CAR33-KLRC1 ko -NK cells demonstrate potent antileukemic killing activity against AML cell lines and primary blasts in vitro and in vivo. We thus conclude that NKG2A-deficient CAR-NK cells have the potential to bypass immune suppression in AML.
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