调控TCR刺激和杀虫剂-α可提高crispr工程人T细胞的基因组安全性。

IF 11.7 1区 医学 Q1 CELL BIOLOGY
Cell Reports Medicine Pub Date : 2024-12-17 Epub Date: 2024-12-04 DOI:10.1016/j.xcrm.2024.101846
Laurenz T Ursch, Jule S Müschen, Julia Ritter, Julia Klermund, Bettina E Bernard, Saskia Kolb, Linda Warmuth, Geoffroy Andrieux, Gregor Miller, Marina Jiménez-Muñoz, Fabian J Theis, Melanie Boerries, Dirk H Busch, Toni Cathomen, Kathrin Schumann
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引用次数: 0

摘要

crispr修饰的嵌合抗原受体(CAR) T细胞处于新型癌症治疗的前沿。然而,一些报道描述了crispr诱导的染色体畸变的发生。到目前为止,提高T细胞产物基因组安全性的措施主要集中在CRISPR-Cas9系统的组成部分,而较少关注T细胞的内在特征,例如它们在T细胞受体(TCR)刺激后的大量扩增。在这里,我们描述了原代人T细胞中indel形成的驱动力。增加的T细胞活化和增殖速度与较大的缺失相关。编辑非活化的T细胞降低了大量缺失的风险,同时降低了敲除效率。或者,添加小分子的杀虫剂-α以p53独立的方式限制了大缺失、染色体易位和非整倍体,同时保持了crispr工程T细胞(包括CAR - T细胞)的功能。控制T细胞活化和氟氯菊酯-α处理是提高crispr工程T细胞基因组完整性的容易实施的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Modulation of TCR stimulation and pifithrin-α improve the genomic safety profile of CRISPR-engineered human T cells.

CRISPR-engineered chimeric antigen receptor (CAR) T cells are at the forefront of novel cancer treatments. However, several reports describe the occurrence of CRISPR-induced chromosomal aberrations. So far, measures to increase the genomic safety of T cell products focused mainly on the components of the CRISPR-Cas9 system and less on T cell-intrinsic features, such as their massive expansion after T cell receptor (TCR) stimulation. Here, we describe driving forces of indel formation in primary human T cells. Increased T cell activation and proliferation speed correlate with larger deletions. Editing of non-activated T cells reduces the risk of large deletions with the downside of reduced knockout efficiencies. Alternatively, the addition of the small-molecule pifithrin-α limits large deletions, chromosomal translocations, and aneuploidy in a p53-independent manner while maintaining the functionality of CRISPR-engineered T cells, including CAR T cells. Controlling T cell activation and pifithrin-α treatment are easily implementable strategies to improve the genomic integrity of CRISPR-engineered T cells.

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来源期刊
Cell Reports Medicine
Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)
CiteScore
15.00
自引率
1.40%
发文量
231
审稿时长
40 days
期刊介绍: Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.
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