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

IF 19.8 1区医学 Q1 CELL & TISSUE ENGINEERING

Cell stem cell Pub Date : 2024-11-05 DOI:10.1016/j.stem.2024.10.004

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, George Q. Daley

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引用次数: 0

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.

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通过化学抑制 G9a/GLP 实现人类多能干细胞 CAR T 细胞的成熟和持久性

阐明T细胞的发育机制可以指导诱导多能干细胞（iPSC）的体外T细胞分化，并促进基于T细胞的现成免疫疗法。利用无基质的人类 iPSC-T 细胞分化平台，我们筛选了影响 T 细胞分化的表观遗传调节剂，并确定了 H3K9 引导的组蛋白甲基转移酶 G9a/GLP 是 T 细胞命运的抑制因子。我们发现，在造血干细胞和祖细胞（HSPCs）分化的特定时间窗口抑制 G9a/GLP 会使细胞命运向淋巴系倾斜。在斑马鱼胚胎造血过程中，抑制 G9a/GLP 可促进淋巴细胞的产生，这证明了 G9a/GLP 功能的进化保护。重要的是，化学抑制 G9a/GLP 可促进成熟 iPSC-T 细胞的生成，这些细胞与外周血 αβ T 细胞具有转录相似性。当被设计表达嵌合抗原受体时，经表观遗传学设计的 iPSC-T 细胞在体外表现出更强的效应功能，并在异种移植肿瘤挑战模型中表现出持久的抗肿瘤活性。

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来源期刊

Cell stem cell 生物-细胞生物学

CiteScore

37.10

自引率

2.50%

发文量

151

审稿时长

42 days

期刊介绍： Cell Stem Cell is a comprehensive journal covering the entire spectrum of stem cell biology. It encompasses various topics, including embryonic stem cells, pluripotency, germline stem cells, tissue-specific stem cells, differentiation, epigenetics, genomics, cancer stem cells, stem cell niches, disease models, nuclear transfer technology, bioengineering, drug discovery, in vivo imaging, therapeutic applications, regenerative medicine, clinical insights, research policies, ethical considerations, and technical innovations. The journal welcomes studies from any model system providing insights into stem cell biology, with a focus on human stem cells. It publishes research reports of significant importance, along with review and analysis articles covering diverse aspects of stem cell research.