肿瘤细胞治疗研究
英文原题：EZH1 repression generates mature iPSC-derived CAR T cells with enhanced antitumor activity.
EZH1 repression generates mature iPSC-derived CAR T cells with enhanced antitumor activity.
人诱导多能干细胞（iPSCs）为细胞治疗提供了潜在无限的资源，但获得成熟细胞类型仍然具有挑战性。
人诱导多能干细胞（iPSCs）为细胞治疗提供了潜在无限的资源，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控因子。在此，我们证明 EZH1 抑制促进了 iPSCs 向 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 来源的 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）库和与外周血 TCR T 细胞相似的成熟分子特征。激活后，EZ-T 细胞产生效应和记忆 T 细胞亚群。当转导嵌合抗原受体（CARs）后，EZ-T 细胞在体外和异种移植模型中表现出强效的抗肿瘤活性。通过 EZH1 抑制进行的表观遗传重塑允许从 iPSCs 高效生产发育成熟的 T 细胞，用于过继性细胞治疗的应用。
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 TCR 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.
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