Deleting SUV39H1 in CAR-T cells epigenetically enhances the antitumor function.
MedComm (2020)
; 5(5): e552, 2024 May.
Article
em En
| MEDLINE
| ID: mdl-38645666
ABSTRACT
SUV39H1 ablation in CAR-T cells epigenetically enhances the antitumor function (by Figdraw). (A) Schematic illustration of SUV39H1 ablation-mediated enhanced antitumor function of CAR-T cells. Functional CAR-T cells eventually transformed into dysfunctional exhausted CAR-T cells under the exposure of chronic tumor antigens, accompanied by reduced proliferation level, effector function, and stemness/memory characteristics, thereby limiting the antitumor activity so as to cause the recurrence of solid tumors. Upon genetic engineering of SUV39H1 ablation, SUV KO CAR-T cells are endowed with increased proliferation level and stemness/memory properties, accompanied by reduced effector/exhausted phenotype. Augmented SUV KO CAR-T cells after in vitro expansion intravenously infusion to mice achieved stronger and more persistent tumor rejection. (B) SUV39H1 ablation-mediated epigenetic reprogramming mechanism of CAR-T cells. Epigenetically, under the stimulation of chronic tumor antigens, exhausted CAR-T cells were characterized by downregulation of proliferation, effector and stemness/memory-associated genes and upregulation of exhaustion-associated genes. SUV39H1 genetic ablation increased chromatin accessibility of stemness/memory-associated genes and reduced chromatin accessibility of inhibitory receptors and effector-associated genes in SUV KO CAR-T cells, epigenetically reprogramming human T cells to express higher levels of stemness/memory genes such as KLF2, LEF1 and TCF7 and lower levels of effector/exhaustion genes.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
MedComm (2020)
Ano de publicação:
2024
Tipo de documento:
Article