期限(时间)
烧蚀
癌症研究
功能(生物学)
生物
实体瘤
化学
细胞生物学
计算生物学
医学
癌症
内科学
物理
量子力学
作者
Sheila López‐Cobo,Jaime R. Fuentealba,Paul Gueguen,Pierre-Emmanuel Bonté,Kyriaki Tsalkitzi,Ignacio Fernández Chacón,Salomé Glauzy,Armelle Bohineust,Ariane Biquand,Lisseth Silva,Zélia Gouveia,Christel Goudot,Franck Perez,Michael Saitakis,Sebastián Amigorena
出处
期刊:Cancer Discovery
[American Association for Cancer Research]
日期:2024-01-03
卷期号:: OF1-OF22
被引量:4
标识
DOI:10.1158/2159-8290.cd-22-1350
摘要
Abstract Failure of adoptive T-cell therapies in patients with cancer is linked to limited T-cell expansion and persistence, even in memory-prone 41BB-(BBz)–based chimeric antigen receptor (CAR) T cells. We show here that BBz-CAR T-cell stem/memory differentiation and persistence can be enhanced through epigenetic manipulation of the histone 3 lysine 9 trimethylation (H3K9me3) pathway. Inactivation of the H3K9 trimethyltransferase SUV39H1 enhances BBz-CAR T cell long-term persistence, protecting mice against tumor relapses and rechallenges in lung and disseminated solid tumor models up to several months after CAR T-cell infusion. Single-cell transcriptomic (single-cell RNA sequencing) and chromatin opening (single-cell assay for transposase accessible chromatin) analyses of tumor-infiltrating CAR T cells show early reprogramming into self-renewing, stemlike populations with decreased expression of dysfunction genes in all T-cell subpopulations. Therefore, epigenetic manipulation of H3K9 methylation by SUV39H1 optimizes the long-term functional persistence of BBz-CAR T cells, limiting relapses, and providing protection against tumor rechallenges. Significance: Limited CAR T-cell expansion and persistence hinders therapeutic responses in solid cancer patients. We show that targeting SUV39H1 histone methyltransferase enhances 41BB-based CAR T-cell long-term protection against tumor relapses and rechallenges by increasing stemness/memory differentiation. This opens a safe path to enhancing adoptive cell therapies for solid tumors. See related article by Jain et al., p. 142.
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