Human induced pluripotent stem cell (iPS cell)-derived chimeric antigen receptor (CAR) T cells hold great therapeutic potential, but often present an immature phenotype compared with αβ T cells used for autologous CAR T cell therapy. A new study shows that H3K9-directed histone methyltransferases G9a–GLP inhibition enables the generation of mature iPS cell-derived T cells.

Jing et al. performed a chemical screen and multiple functional experiments using a stroma-free human iPS cell–T cell differentiation protocol and found that UNC0224, an inhibitor of the histone lysine methyltransferase G9a–GLP complex, enhances the commitment of haematopoietic stem and progenitor cells into lymphoid fates. Chromatin accessibility and transcriptomics analyses indicated that G9a–GLP regulates lymphoid genes. Importantly, Jing et al. then showed that UNC0224 treatment increased the iPS cell-derived mature CD8α⁺CD8β⁺αβTCR⁺ T cells and their transcriptional resemblance to peripheral blood T cells. Finally, experiments including a xenograft tumour model indicated that CAR T cells produced upon UNC0224 treatment achieve higher tumour clearance and improve survival.

人诱导多能干细胞 （iPS 细胞） 衍生的嵌合抗原受体 （CAR） T 细胞具有巨大的治疗潜力，但与用于自体 CAR T 细胞疗法的 αβ T 细胞相比，通常表现出不成熟的表型。一项新的研究表明，H3K9 定向组蛋白甲基转移酶 G9a-GLP 抑制能够产生成熟的 iPS 细胞衍生的 T 细胞。

Jing 等人使用无基质的人 iPS 细胞-T 细胞分化方案进行了化学筛选和多种功能实验，发现 UNC0224 是组蛋白赖氨酸甲基转移酶 G9a-GLP 复合物的抑制剂，可增强造血干细胞和祖细胞对淋巴细胞命运的定型。染色质可及性和转录组学分析表明，G9a-GLP 调节淋巴基因。重要的是，Jing 等人随后表明，UNC0224处理增加了 iPS 细胞衍生的成熟 CD8α⁺CD8β⁺αβTCR⁺ T 细胞及其与外周血 T 细胞的转录相似性。最后，包括异种移植肿瘤模型的实验表明，UNC0224治疗后产生的 CAR T 细胞可实现更高的肿瘤清除率并提高生存率。