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

Cell Differentiation Humans Immunotherapy, Adoptive Induced Pluripotent Stem Cells / metabolism Polycomb Repressive Complex 2 / metabolism Receptors, Chimeric Antigen / metabolism T-Lymphocytes
CAR T cells EZH1 T cell differentiation cancer immunotherapy hematopoietic stem and progenitor cells pluripotent stem cells

Journal

Cell stem cell
ISSN: 1875-9777
Titre abrégé: Cell Stem Cell
Pays: United States
ID NLM: 101311472

Informations de publication

Date de publication:
04 08 2022
Historique:
received: 02 02 2022
revised: 31 05 2022
accepted: 29 06 2022
pubmed: 6 8 2022
medline: 10 8 2022
entrez: 5 8 2022
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.stem.2022.06.014 PMID: 35931029 PMC: PMC9386785
pubmed: 35931029
pii: S1934-5909(22)00295-8
doi: 10.1016/j.stem.2022.06.014
pmc: PMC9386785
mid: NIHMS1826137
pii:
doi:

Substances chimiques

Receptors, Chimeric Antigen 0
EZH1 protein, human EC 2.1.1.43
Polycomb Repressive Complex 2 EC 2.1.1.43

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

1181-1196.e6

Subventions

Organisme : NIDDK NIH HHS
ID : UC4 DK104218
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL134812
Pays : United States
Organisme : NHLBI NIH HHS
ID : R13 HL104873
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK070055
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL071265
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM107536
Pays : United States
Organisme : NIDDK NIH HHS
ID : R24 DK092760
Pays : United States
Organisme : NIDDK NIH HHS
ID : RC2 DK120535
Pays : United States
Organisme : NIDDK NIH HHS
ID : RC4 DK090913
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK104218
Pays : United States
Organisme : NHLBI NIH HHS
ID : U24 HL134763
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL100001
Pays : United States
Organisme : NHLBI NIH HHS
ID : RC2 HL102815
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2022 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests R.J., G.Q.D., and Boston Children’s Hospital hold intellectual property and receive consulting fees and/or hold equity interest relevant to the generation of iPSC-derived T cells. T.M.S. receives sponsored research support from Elevate Bio. G.Q.D. is a member of Cell Stem Cell’s advisory board.

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Auteurs

Ran Jing (R)

Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

Irene Scarfo (I)

Cellular Immunotherapy Program, Massachusetts General Hospital Cancer Center, Charlestown, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.

Mohamad Ali Najia (MA)

Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard-MIT Health Sciences & Technology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.

Edroaldo Lummertz da Rocha (E)

Department of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianópolis, SC 88040-900, Brazil.

Areum Han (A)

Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

Michael Sanborn (M)

Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA.

Trevor Bingham (T)

Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA.

Caroline Kubaczka (C)

Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

Deepak K Jha (DK)

Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

Marcelo Falchetti (M)

Graduate Program of Pharmacology, Center for Biological Sciences, Federal University of Santa Catarina, Florianópolis, SC 88040-900, Brazil.

Thorsten M Schlaeger (TM)

Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, MA 02115, USA.

Trista E North (TE)

Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, MA 02115, USA; Developmental and Regenerative Biology Program, Harvard Medical School, Boston, MA 02115, USA.

Marcela V Maus (MV)

Cellular Immunotherapy Program, Massachusetts General Hospital Cancer Center, Charlestown, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.

George Q Daley (GQ)

Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, MA 02115, USA; Developmental and Regenerative Biology Program, Harvard Medical School, Boston, MA 02115, USA. Electronic address: george.daley@childrens.harvard.edu.

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Classifications MeSH

questionsmedicales.fr › Phénomènes physiologiques cellulaires › Différenciation cellulaire › EZH1 repression generates mature iPSC-derived...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › EZH1 repression generates mature iPSC-derived...
questionsmedicales.fr › Techniques d'investigation › Techniques immunologiques › Immunisation passive › Transfert adoptif › Immunothérapie adoptive › EZH1 repression generates mature iPSC-derived...
questionsmedicales.fr › Cellules › Cellules souches › Cellules souches pluripotentes › Cellules souches pluripotentes induites › EZH1 repression generates mature iPSC-derived...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Protéines de répression › Protéines du groupe Polycomb › Complexe répresseur Polycomb-2 › EZH1 repression generates mature iPSC-derived...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Récepteurs cytoplasmiques et nucléaires › Récepteurs chimériques pour l'antigène › EZH1 repression generates mature iPSC-derived...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Leucocytes › Agranulocytes › Lymphocytes › Lymphocytes T › EZH1 repression generates mature iPSC-derived...