嵌合抗原受体
表观遗传学
生物
效应器
癌症研究
H3K4me3
CD28
组蛋白
EZH2型
DNA甲基化
T细胞
过继性细胞移植
细胞生物学
免疫学
遗传学
免疫系统
发起人
基因表达
基因
作者
Nayan Jain,Zeguo Zhao,Richard P. Koche,Chenling Antelope,Yosi Gozlan,Antonino Montalbano,David Brocks,Michael Lopez,Anton Dobrin,Yuzhe Shi,Gertrude Gunset,Theodoros Giavridis,Michel Sadelain
出处
期刊:Cancer Discovery
[American Association for Cancer Research]
日期:2023-10-31
卷期号:14 (1): 142-157
被引量:3
标识
DOI:10.1158/2159-8290.cd-22-1319
摘要
Suboptimal functional persistence limits the efficacy of adoptive T-cell therapies. CD28-based chimeric antigen receptors (CAR) 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 antitumor 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.T cells engineered with CD28-based CARs possess robust effector function and antigen sensitivity but are hampered by limited persistence, which may result in tumor relapse. We report an epigenetic strategy involving disruption of the SUV39H1-mediated histone-silencing program that promotes the functional persistence of CD28-based CAR T cells. See related article by López-Cobo et al., p. 120. This article is featured in Selected Articles from This Issue, p. 5.
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