EZH1 Repression Generates Mature IPSC-derived CAR T cells with Enhanced Antitumor Activity

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2022 Aug 5

PMID 35931029

Authors

Ran Jing

Irene Scarfo

Mohamad Ali Najia

Edroaldo Lummertz da Rocha

Areum Han

Michael Sanborn

Trevor Bingham

Caroline Kubaczka

Deepak K Jha

Marcelo Falchetti

Thorsten M Schlaeger

Trista E North

Marcela V Maus

George Q Daley

Affiliations

Soon will be listed here.

Abstract

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.

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