Ablation of FAS confers allogeneic CD3– CAR T cells with resistance to rejection by T cells and natural killer cells

IF 26.8 1区医学 Q1 ENGINEERING, BIOMEDICAL

Nature Biomedical Engineering Pub Date : 2024-11-18 DOI:10.1038/s41551-024-01282-8

Silvia Menegatti, Sheila Lopez-Cobo, Aurelien Sutra Del Galy, Jaime Fuentealba, Lisseth Silva, Laetitia Perrin, Sandrine Heurtebise-Chrétien, Valentine Pottez-Jouatte, Aurelie Darbois, Nina Burgdorf, Anne-Laure Privat, Albane Simon, Marguerite Laprie-Sentenac, Michael Saitakis, Bryce Wick, Beau R. Webber, Branden S. Moriarity, Olivier Lantz, Sebastian Amigorena, Laurie Menger

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Abstract

Allogeneic chimaeric antigen receptor T cells (allo-CAR T cells) derived from healthy donors could provide rapid access to standardized and affordable batches of therapeutic cells if their rejection by the host’s immune system is avoided. Here, by means of an in vivo genome-wide CRISPR knockout screen, we show that the deletion of Fas or B2m in allo- T cells increases their survival in immunocompetent mice. Human B2M^– allo-CAR T cells become highly sensitive to rejection mediated by natural killer (NK) cells, whereas FAS^– CAR T cells expressing normal levels of human leukocyte antigen I remain resistant to NK cells. CD3^– FAS^– CAR T cells outperformed CD3^– B2M^– CAR T cells in the control of leukaemia growth in mice under allogeneic pressure by T cells and NK cells. The partial protection of CD3^– FAS^– allo-CAR T cells from cellular rejection may improve the efficacy of allogeneic cellular therapies in patients with cancer.

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消融 FAS 使异体 CD3- CAR T 细胞具有抗 T 细胞和自然杀伤细胞排斥的能力

如果能避免宿主免疫系统对异体抗原受体 T 细胞（allo-CAR T 细胞）的排斥反应，那么从健康供体中提取的异体嵌合抗原受体 T 细胞（allo-CAR T 细胞）就能为人们提供快速获取标准化且价格合理的治疗细胞的途径。在这里，我们通过体内全基因组 CRISPR 基因敲除筛选表明，在allo-T 细胞中删除 Fas 或 B2m 能提高它们在免疫功能正常小鼠体内的存活率。人类 B2M- allo-CAR T 细胞对自然杀伤（NK）细胞介导的排斥反应高度敏感，而表达正常水平人类白细胞抗原 I 的 FAS- CAR T 细胞对 NK 细胞仍有抵抗力。在 T 细胞和 NK 细胞的异体压力下，CD3- FAS- CAR T 细胞在控制小鼠白血病生长方面优于 CD3- B2M- CAR T 细胞。CD3- FAS- allo-CAR T 细胞对细胞排斥反应的部分保护作用可能会提高癌症患者接受异体细胞疗法的疗效。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature Biomedical Engineering Medicine-Medicine (miscellaneous)

CiteScore

45.30

自引率

1.10%

发文量

138

期刊介绍： Nature Biomedical Engineering is an online-only monthly journal that was launched in January 2017. It aims to publish original research, reviews, and commentary focusing on applied biomedicine and health technology. The journal targets a diverse audience, including life scientists who are involved in developing experimental or computational systems and methods to enhance our understanding of human physiology. It also covers biomedical researchers and engineers who are engaged in designing or optimizing therapies, assays, devices, or procedures for diagnosing or treating diseases. Additionally, clinicians, who make use of research outputs to evaluate patient health or administer therapy in various clinical settings and healthcare contexts, are also part of the target audience.