衰老性 CAR T 细胞可逆转衰老相关病症

IF 50.5 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
Nature Pub Date : 2020-06-17 DOI:10.1038/s41586-020-2403-9
Corina Amor, Judith Feucht, Josef Leibold, Yu-Jui Ho, Changyu Zhu, Direna Alonso-Curbelo, Jorge Mansilla-Soto, Jacob A. Boyer, Xiang Li, Theodoros Giavridis, Amanda Kulick, Shauna Houlihan, Ellinor Peerschke, Scott L. Friedman, Vladimir Ponomarev, Alessandra Piersigilli, Michel Sadelain, Scott W. Lowe
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引用次数: 398

摘要

细胞衰老的特点是稳定的细胞周期停滞和调节组织微环境的分泌程序1,2。在生理学上,衰老是一种肿瘤抑制机制,可防止癌前细胞的扩张3,4 ,并在伤口愈合反应中发挥有益作用5,6。在病理上,衰老细胞的异常积累会产生炎症环境,导致慢性组织损伤,并引发肝脏和肺部纤维化、动脉粥样硬化、糖尿病和骨关节炎等疾病1,7。因此,消除小鼠受损组织中的衰老细胞可改善这些病症的症状,甚至促进长寿1,2,8-10。在这里,我们测试了针对衰老细胞的嵌合抗原受体(CAR)T 细胞可以成为有效的衰老溶解剂这一治疗理念。我们发现尿激酶型纤溶酶原激活物受体(uPAR)11 是衰老过程中广泛诱导的细胞表面蛋白,并证明uPAR 特异性 CAR T 细胞能在体外和体内有效消融衰老细胞。靶向 uPAR 的 CAR T 细胞延长了接受衰老诱导联合药物治疗的肺腺癌小鼠的存活时间,并恢复了化学或饮食诱导肝纤维化小鼠的组织稳态。这些结果证实了衰老性 CAR T 细胞对衰老相关疾病的治疗潜力。嵌合抗原受体(CAR)T细胞靶向衰老细胞上调的细胞表面蛋白uPAR,在体外和体内消除衰老细胞,减轻小鼠肝纤维化。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Senolytic CAR T cells reverse senescence-associated pathologies

Senolytic CAR T cells reverse senescence-associated pathologies
Cellular senescence is characterized by stable cell-cycle arrest and a secretory program that modulates the tissue microenvironment1,2. Physiologically, senescence serves as a tumour-suppressive mechanism that prevents the expansion of premalignant cells3,4 and has a beneficial role in wound-healing responses5,6. Pathologically, the aberrant accumulation of senescent cells generates an inflammatory milieu that leads to chronic tissue damage and contributes to diseases such as liver and lung fibrosis, atherosclerosis, diabetes and osteoarthritis1,7. Accordingly, eliminating senescent cells from damaged tissues in mice ameliorates the symptoms of these pathologies and even promotes longevity1,2,8–10. Here we test the therapeutic concept that chimeric antigen receptor (CAR) T cells that target senescent cells can be effective senolytic agents. We identify the urokinase-type plasminogen activator receptor (uPAR)11 as a cell-surface protein that is broadly induced during senescence and show that uPAR-specific CAR T cells efficiently ablate senescent cells in vitro and in vivo. CAR T cells that target uPAR extend the survival of mice with lung adenocarcinoma that are treated with a senescence-inducing combination of drugs, and restore tissue homeostasis in mice in which liver fibrosis is induced chemically or by diet. These results establish the therapeutic potential of senolytic CAR T cells for senescence-associated diseases. Chimeric antigen receptor (CAR) T cells targeting uPAR, a cell-surface protein that is upregulated on senescent cells, eliminate senescent cells in vitro and in vivo and reduce liver fibrosis in mice.
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来源期刊
Nature
Nature 综合性期刊-综合性期刊
CiteScore
90.00
自引率
1.20%
发文量
3652
审稿时长
3 months
期刊介绍: Nature is a prestigious international journal that publishes peer-reviewed research in various scientific and technological fields. The selection of articles is based on criteria such as originality, importance, interdisciplinary relevance, timeliness, accessibility, elegance, and surprising conclusions. In addition to showcasing significant scientific advances, Nature delivers rapid, authoritative, insightful news, and interpretation of current and upcoming trends impacting science, scientists, and the broader public. The journal serves a dual purpose: firstly, to promptly share noteworthy scientific advances and foster discussions among scientists, and secondly, to ensure the swift dissemination of scientific results globally, emphasizing their significance for knowledge, culture, and daily life.
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