CAR-T（CAR-T）细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CAR-T（CAR-T）细胞在血液系统恶性肿瘤中的应用推动了这种免疫治疗形式的显著进展。
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
CAR-T 细胞的表观遗传重编程以实现针对实体瘤的体内功能持久性
英文原题：Epigenetic reprogramming of CAR T cells for in vivo functional persistence against solid tumors.
查看英文原题
Epigenetic reprogramming of CAR T cells for in vivo functional persistence against solid tumors.
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中文摘要
有限的 CAR-T 细胞扩增和持久性阻碍了实体瘤患者的治疗反应。为了增强工程化 T 细胞疗法的功能性持久性，我们在人 CAR-T 细胞中对 SUV39H1 进行了基因敲除，SUV39H1 是一种促进异染色质形成的组蛋白 3 赖氨酸 9 甲基转移酶。这导致了表型上的 CAR-T 重编程，从而产生了最佳且持续的抗肿瘤功能。对肿瘤浸润性 CAR-T 细胞的单细胞转录组（scRNA-seq）和染色质可及性（scATAC-seq）分析显示，所有亚群均早期重编程为自我更新的干细胞样群体，且功能障碍基因表达降低。此外，我们提供了证据表明，SUV39H1 失活可在多次肿瘤再攻击后引发强效且持久的功能性持久性。这为增强实体瘤的过继性细胞疗法开辟了一条安全的路径。
展开英文摘要原文
Limited CAR T-cell expansion and persistence hinder therapeutic responses in solid cancer patients. To enhance the functional persistence of engineered T-cell therapies, we performed genetic disruption in human CAR T cells of SUV39H1, a histone 3 lysine 9 methyltransferase that promotes heterochromatin formation.
This resulted in phenotypic CAR-T reprogramming that elicited optimal and sustained antitumor functionality. Single-cell transcriptomic (scRNA-seq) and chromatin accessibility (scATAC-seq) analyses of tumor-infiltrating CAR T cells showed early reprogramming into self-renewing, stem-like populations with decreased expression of dysfunction genes in all subpopulations.
Moreover, we provided evidence that SUV39H1 inactivation elicits potent and durable functional persistence upon multiple tumor rechallenges. This opens a safe path to enhancing adoptive cell therapies for solid tumors.
论文信息
- 作者
- Saitakis M
- 单位
- Mnemo Therapeutics, 101 Boulevard Murat, 75016, Paris, France. michael.saitakis@mnemo-tx.com.France
- 期刊
- Genes and immunity2024 Oct
- 原文标识
- PubMed 38388813 · DOI 10.1038/s41435-024-00262-x