EZH1 repression generates mature iPSC-derived CAR T cells with enhanced antitumor activity

Cell Stem Cell. 2022 Aug 4;29(8):1181-1196.e6. doi: 10.1016/j.stem.2022.06.014.


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.

Keywords: CAR T cells; EZH1; T cell differentiation; cancer immunotherapy; hematopoietic stem and progenitor cells; pluripotent stem cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Differentiation
  • Humans
  • Immunotherapy, Adoptive
  • Induced Pluripotent Stem Cells* / metabolism
  • Polycomb Repressive Complex 2 / metabolism
  • Receptors, Chimeric Antigen* / metabolism
  • T-Lymphocytes


  • Receptors, Chimeric Antigen
  • EZH1 protein, human
  • Polycomb Repressive Complex 2