Disruption of SUV39H1-mediated H3K9 methylation sustains CAR T cell function.
Nayan JainZeguo ZhaoRichard P KocheChenling A XuYosi GozlanAntonino MontalbanoDavid BrocksMichael LopezAnton DobrinYuzhe ShiGertrude GunsetTheodoros GiavridisMichel SadelainPublished in: Cancer discovery (2023)
Suboptimal functional persistence limits the efficacy of adoptive T cell therapies. CD28-based chimeric antigen receptors (CARs) impart potent effector function to T cells but with a limited lifespan. We show here that the genetic disruption of SUV39H1, which encodes a histone-3, lysine-9 methyl-transferase, enhances the early expansion, long-term persistence, and overall anti-tumor efficacy of human CAR T cells in leukemia and prostate cancer models. Persisting SUV39H1-edited CAR T cells demonstrate improved expansion and tumor rejection upon multiple rechallenges. Transcriptional and genome accessibility profiling of repeatedly challenged CAR T cells shows improved expression and accessibility of memory transcription factors in SUV39H1-edited CAR T cells. SUV39H1 editing also reduces expression of inhibitory receptors and limits exhaustion in CAR T cells that have undergone multiple rechallenges. Our findings thus demonstrate the potential of epigenetic programming of CAR T cells to balance their function and persistence for improved adoptive cell therapies.
Keyphrases
- cell therapy
- crispr cas
- prostate cancer
- dna methylation
- poor prognosis
- transcription factor
- genome wide
- gene expression
- single cell
- endothelial cells
- stem cells
- acute myeloid leukemia
- bone marrow
- binding protein
- radical prostatectomy
- working memory
- climate change
- long non coding rna
- dendritic cells
- oxidative stress
- dna binding
- amino acid