PUBLICATION
Maturation and persistence of CAR T cells derived from human pluripotent stem cells via chemical inhibition of G9a/GLP
- Authors
- Jing, R., Falchetti, M., Han, T., Najia, M., Hensch, L.T., Meader, E., Lummertz da Rocha, E., Kononov, M., Wang, S., Bingham, T., Li, Z., Zhao, Y., Frenis, K., Kubaczka, C., Yang, S., Jha, D., Rodrigues-Luiz, G.F., Rowe, R.G., Schlaeger, T.M., Maus, M.V., North, T.E., Zon, L.I., Daley, G.Q.
- ID
- ZDB-PUB-241107-6
- Date
- 2024
- Source
- Cell Stem Cell 32(1): 71-85.e5 (Journal)
- Registered Authors
- North, Trista, Schlaeger, Thorsten, Zon, Leonard I.
- Keywords
- CAR-T cells, G9a/GLP, T cell differentiation, cancer immunotherapy, chemical screen, epigenetic regulation, hematopoiesis, lymphoid development, pluripotent stem cells
- MeSH Terms
-
- Receptors, Chimeric Antigen/metabolism
- Zebrafish*
- Animals
- T-Lymphocytes*/cytology
- T-Lymphocytes*/immunology
- T-Lymphocytes*/metabolism
- Histone-Lysine N-Methyltransferase*/antagonists & inhibitors
- Histone-Lysine N-Methyltransferase*/metabolism
- Mice
- Cell Differentiation*/drug effects
- Pluripotent Stem Cells/cytology
- Pluripotent Stem Cells/metabolism
- Humans
- Induced Pluripotent Stem Cells/cytology
- Induced Pluripotent Stem Cells/metabolism
- Histocompatibility Antigens/metabolism
- PubMed
- 39504968 Full text @ Cell Stem Cell
Citation
Jing, R., Falchetti, M., Han, T., Najia, M., Hensch, L.T., Meader, E., Lummertz da Rocha, E., Kononov, M., Wang, S., Bingham, T., Li, Z., Zhao, Y., Frenis, K., Kubaczka, C., Yang, S., Jha, D., Rodrigues-Luiz, G.F., Rowe, R.G., Schlaeger, T.M., Maus, M.V., North, T.E., Zon, L.I., Daley, G.Q. (2024) Maturation and persistence of CAR T cells derived from human pluripotent stem cells via chemical inhibition of G9a/GLP. Cell Stem Cell. 32(1):71-85.e5.
Abstract
Elucidating mechanisms of T cell development can guide in vitro T cell differentiation from induced pluripotent stem cells (iPSCs) and facilitate off-the-shelf T cell-based immunotherapies. Using a stroma-free human iPSC-T cell differentiation platform, we screened for epigenetic modulators that influence T cell specification and identified the H3K9-directed histone methyltransferases G9a/GLP as repressors of T cell fate. We show that G9a/GLP inhibition during specific time windows of differentiation of hematopoietic stem and progenitor cells (HSPCs) skews cell fates toward lymphoid lineages. Inhibition of G9a/GLP promotes the production of lymphoid cells during zebrafish embryonic hematopoiesis, demonstrating the evolutionary conservation of G9a/GLP function. Importantly, chemical inhibition of G9a/GLP facilitates the generation of mature iPSC-T cells that bear transcriptional similarity to peripheral blood αβ T cells. When engineered to express chimeric antigen receptors, the epigenetically engineered iPSC-T cells exhibit enhanced effector functions in vitro and durable, persistent antitumor activity in a xenograft tumor-rechallenge model.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping