Senolytic CAR T cells reverse senescence-associated pathologies.
Senolytic CAR T cells reverse senescence-associated pathologies.
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DOI：
10.1038/s41586-020-2403-9
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发表时间：
2020-07
期刊：
影响因子：
64.8
通讯作者：
Lowe SW
中科院分区：
文献类型：
--
作者：
Amor C;Feucht J;Leibold J;Ho YJ;Zhu C;Alonso-Curbelo D;Mansilla-Soto J;Boyer JA;Li X;Giavridis T;Kulick A;Houlihan S;Peerschke E;Friedman SL;Ponomarev V;Piersigilli A;Sadelain M;Lowe SW
细胞衰老的特征是稳定的细胞周期停滞和调节组织微环境的分泌程序。从生理上讲，衰老是一种肿瘤抑制机制，可以阻止癌前细胞的扩张，并在伤口愈合反应中发挥有益的作用。在病理学上，衰老细胞的异常聚集会产生炎症环境，导致慢性组织损伤，并导致肝和肺纤维化、动脉粥样硬化、糖尿病和骨关节炎等疾病。因此，清除老鼠受损组织中的衰老细胞可以缓解这些病理症状，甚至可以延长寿命。在这里，我们测试了嵌合抗原受体(CAR)T细胞靶向衰老细胞可以是有效的感觉剂的治疗概念。我们发现尿激酶型纤溶酶原激活剂受体(UPAR)是衰老过程中广泛诱导的一种细胞表面蛋白，并在体外和体内证明了uPAR特异性CAR T细胞有效地消融衰老细胞。UPAR导向的CAR T细胞延长了携带肺腺癌的小鼠的存活时间，并恢复了化学或饮食诱导的肝纤维化中的组织动态平衡。这些结果确立了衰老相关疾病的CAR T细胞的治疗潜力。
Cellular senescence is characterized by stable cell cycle arrest and a secretory program that modulates the tissue microenvironment. Physiologically, senescence serves as a tumor suppressive mechanism that prevents the expansion of premalignant cells and plays a beneficial role in wound healing responses. 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 osteoarthritis. Accordingly, elimination of senescent cells from damaged tissues in mice ameliorates symptoms of these pathologies and even promotes longevity. Here we test the therapeutic concept that chimeric antigen receptor (CAR) T cells targeting senescent cells can be effective senolytics. We identify the urokinase plasminogen activator receptor (uPAR) as a cell surface protein broadly induced during senescence and demonstrate that uPAR-specific CAR T cells efficiently ablate senescent cells in vitro and in vivo. uPAR-directed CAR T cells extend the survival of mice harboring lung adenocarcinoma treated with a senescence-inducing drug combination, and restore tissue homeostasis in chemical- or diet-induced liver fibrosis. These results establish the therapeutic potential of senolytic CAR T cells for senescence-associated diseases.
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影响因子：
82.9
作者：
Giavridis T;van der Stegen SJC;Eyquem J;Hamieh M;Piersigilli A;Sadelain M
通讯作者：
Sadelain M
影响因子：
27.4
作者：
Belcher, C;Fawthrop, F;Doherty, M
通讯作者：
Doherty, M
影响因子：
64.8
作者：
Kang, Tae-Won;Yevsa, Tetyana;Zender, Lars
通讯作者：
Zender, Lars
影响因子：
3.7
作者：
Davila ML;Kloss CC;Gunset G;Sadelain M
通讯作者：
Sadelain M
影响因子：
50.3
作者：
Anderson KG;Stromnes IM;Greenberg PD
通讯作者：
Greenberg PD