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.
复制标题
EZH1阻遏产生具有增强的抗肿瘤活性的成熟iPSC衍生的CAR T细胞。
DOI：
10.1016/j.stem.2022.06.014
复制
发表时间：
2022-08-04
期刊：
影响因子：
23.9
通讯作者：
Daley, George Q.
中科院分区：
文献类型：
--
作者：
Jing, Ran;Scarfo, Irene;Najia, Mohamad Ali;da Rocha, Edroaldo Lummertz;Han, Areum;Sanborn, Michael;Bingham, Trevor;Kubaczka, Caroline;Jha, Deepak K.;Falchetti, Marcelo;Schlaeger, Thorsten M.;North, Trista E.;Maus, Marcela, V;Daley, George Q.
关键词：
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。将无基质的 T 细胞分化系统与 EZH1 敲低介导的表观遗传重编程结合起来，我们生成了 iPSC 衍生的 T 细胞，称为 EZ-T 细胞，它表现出高度多样化的 T 细胞受体 (TCR) 库和与外周血中的 TCRαβ T 细胞相似的成熟分子特征。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。静等人。将无基质分化系统与 EZH1 抑制介导的表观遗传重编程相结合，生成发育成熟的 iPSC 衍生的 CAR T 细胞，并增强抗肿瘤活性。
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, that 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. Jing et al. combine a stroma-free differentiation system with EZH1-repression mediated epigenetic reprogramming to generate developmentally mature iPSC-derived CAR T cells with enhances antitumor activities.
登录
查看更多内容
影响因子：
12.3
作者：
Dang Y;Jia G;Choi J;Ma H;Anaya E;Ye C;Shankar P;Wu H
通讯作者：
Wu H
影响因子：
23.9
作者：
Doulatov, Sergei;Vo, Linda T.;Chou, Stephanie S.;Kim, Peter G.;Arora, Natasha;Li, Hu;Hadland, Brandon K.;Bernstein, Irwin D.;Collins, James J.;Zon, Leonard I.;Daley, George Q.
通讯作者：
Daley, George Q.
影响因子：
21.3
作者：
Ditadi A;Sturgeon CM;Tober J;Awong G;Kennedy M;Yzaguirre AD;Azzola L;Ng ES;Stanley EG;French DL;Cheng X;Gadue P;Speck NA;Elefanty AG;Keller G
通讯作者：
Keller G
影响因子：
64.5
作者：
Good CR;Aznar MA;Kuramitsu S;Samareh P;Agarwal S;Donahue G;Ishiyama K;Wellhausen N;Rennels AK;Ma Y;Tian L;Guedan S;Alexander KA;Zhang Z;Rommel PC;Singh N;Glastad KM;Richardson MW;Watanabe K;Tanyi JL;O'Hara MH;Ruella M;Lacey SF;Moon EK;Schuster SJ;Albelda SM;Lanier LL;Young RM;Berger SL;June CH
通讯作者：
June CH
影响因子：
64.8
作者：
Eyquem J;Mansilla-Soto J;Giavridis T;van der Stegen SJ;Hamieh M;Cunanan KM;Odak A;Gönen M;Sadelain M
通讯作者：
Sadelain M