EZH1 repression promotes generation of mature iPSC-derived CAR T cells with enhanced antitumor activity

Human induced pluripotent stem cells (iPSCs) provide a potentially unlimited resource for cell therapies, but the derivation of functionally mature cell types remains challenging. The histone methyltransferase EZH1 is a negative regulator of lymphoid potential during embryonic hematopoietic development. Here we demonstrate that EZH1 repression facilitates in vitro differentiation and developmental maturation of T cells from iPSCs. Using a stroma-free T cell differentiation system and 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 both effector and memory T cell subsets. When transduced with anti-CD19 chimeric antigen receptors (CARs), EZ-T cells exhibit enhanced anti-tumor activities in vitro and in xenograft models relative to T cells derived by previously established protocols. Epigenetic remodeling via EZH1 repression allows efficient production of developmentally mature T cells from iPSCs for applications in adoptive T cell therapy. EZH1 repression