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EZH1 repression generates mature iPSC-derived CAR T cells with enhanced antitumor activity
Cell Stem Cell ( IF 23.9 ) Pub Date : 2022-08-04 , DOI: 10.1016/j.stem.2022.06.014
Ran Jing 1 , Irene Scarfo 2 , Mohamad Ali Najia 3 , Edroaldo Lummertz da Rocha 4 , Areum Han 1 , Michael Sanborn 5 , Trevor Bingham 5 , Caroline Kubaczka 1 , Deepak K Jha 1 , Marcelo Falchetti 6 , Thorsten M Schlaeger 7 , Trista E North 8 , Marcela V Maus 2 , George Q Daley 9
Affiliation  

Human induced pluripotent stem cells (iPSCs) provide a potentially unlimited resource for cell therapies, but the derivation of mature cell types remains challenging. The histone methyltransferase EZH1 is a negative regulator of lymphoid potential during embryonic hematopoiesis. Here, we demonstrate that EZH1 repression facilitates in vitro differentiation and maturation of T cells from iPSCs. Coupling a stroma-free T cell differentiation system with EZH1-knockdown-mediated epigenetic reprogramming, we generated iPSC-derived T cells, termed EZ-T cells, which display a highly diverse T cell receptor (TCR) repertoire and mature molecular signatures similar to those of TCRαβ T cells from peripheral blood. Upon activation, EZ-T cells give rise to effector and memory T cell subsets. When transduced with chimeric antigen receptors (CARs), EZ-T cells exhibit potent antitumor activities in vitro and in xenograft models. Epigenetic remodeling via EZH1 repression allows efficient production of developmentally mature T cells from iPSCs for applications in adoptive cell therapy.



中文翻译:

EZH1 抑制产生成熟的 iPSC 衍生的 CAR T 细胞,具有增强的抗肿瘤活性

人类诱导多能干细胞(iPSC)为细胞疗法提供了潜在的无限资源,但成熟细胞类型的衍生仍然具有挑战性。组蛋白甲基转移酶 EZH1 是胚胎造血过程中淋巴潜能的负调节因子。在这里,我们证明 EZH1 抑制促进iPSC 中 T 细胞的体外分化和成熟。将无基质 T 细胞分化系统与 EZH1 敲低介导的表观遗传重编程相结合,我们生成了 iPSC 衍生的 T 细胞,称为 EZ-T 细胞,其显示出高度多样化的 T 细胞受体 (TCR) 库和类似于来自外周血的 TCRαβ T 细胞。激活后,EZ-T 细胞会产生效应 T 细胞和记忆 T 细胞亚群。当用嵌合抗原受体 (CAR) 转导时,EZ-T 细胞在体外和异种移植模型中表现出有效的抗肿瘤活性。通过 EZH1 抑制进行表观遗传重塑,可以从 iPSC 中高效生产发育成熟的 T 细胞,用于过继细胞治疗。

更新日期:2022-08-05
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