美国波士顿儿童医院George Q. Daley团队发现，通过化学抑制G9a/GLP可促进来源于人类多能干细胞的CAR T细胞的成熟和持久性。相关论文于2024年11月5日在线发表在《细胞—干细胞》杂志上。

利用一种无基质的人类诱导性多能干细胞（iPSC）-T细胞分化平台，研究人员筛选了影响T细胞分化的表观遗传调节因子，并确定了H3K9定向的组蛋白甲基转移酶G9a/GLP作为T细胞命运的抑制因子。研究人员发现，在造血干细胞和祖细胞（HSPC）分化的特定时间窗口内抑制G9a/GLP可使细胞命运倾向于淋巴谱系。

G9a/GLP的抑制促进了斑马鱼胚胎造血过程中淋巴细胞的生成，证明了G9a/GLP功能的演化保守性。重要的是，化学抑制G9a/GLP促进了成熟iPSC-T细胞的生成，这些细胞在转录水平上与外周血αβ T细胞相似。

当这些细胞被工程化表达嵌合抗原受体时，表观遗传工程改造的iPSC-T细胞在体外展现出增强的效应功能，并在异种移植肿瘤重挑战模型中表现出持久的抗肿瘤活性。

据悉，阐明T细胞发育机制可以指导iPSC中T细胞的体外分化，并促进现成的T细胞免疫疗法。

附：英文原文

Title: Maturation and persistence of CAR T cells derived from human pluripotent stem cells via chemical inhibition of G9a/GLP

Author: Ran Jing, Marcelo Falchetti, Tianxiao Han, Mohamad Najia, Luca T. Hensch, Eleanor Meader, Edroaldo Lummertz da Rocha, Martin Kononov, Stephanie Wang, Trevor Bingham, Zhiheng Li, Yunliang Zhao, Katie Frenis, Caroline Kubaczka, Song Yang, Deepak Jha, Gabriela F. Rodrigues-Luiz, R. Grant Rowe, Thorsten M. Schlaeger, Marcela V. Maus, Trista E. North, Leonard I. Zon, George Q. Daley

Issue&Volume: 2024-11-05

Abstract: Elucidating mechanisms of T cell development can guide in vitro T cell differentiation from induced pluripotent stem cells (iPSCs) and facilitate off-the-shelf T cell-based immunotherapies. Using a stroma-free human iPSC-T cell differentiation platform, we screened for epigenetic modulators that influence T cell specification and identified the H3K9-directed histone methyltransferases G9a/GLP as repressors of T cell fate. We show that G9a/GLP inhibition during specific time windows of differentiation of hematopoietic stem and progenitor cells (HSPCs) skews cell fates toward lymphoid lineages. Inhibition of G9a/GLP promotes the production of lymphoid cells during zebrafish embryonic hematopoiesis, demonstrating the evolutionary conservation of G9a/GLP function. Importantly, chemical inhibition of G9a/GLP facilitates the generation of mature iPSC-T cells that bear transcriptional similarity to peripheral blood αβ T cells. When engineered to express chimeric antigen receptors, the epigenetically engineered iPSC-T cells exhibit enhanced effector functions in vitro and durable, persistent antitumor activity in a xenograft tumor-rechallenge model.

DOI: 10.1016/j.stem.2024.10.004

Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(24)00366-7