Cellular senescence is characterized by stable cell-cycle arrest and a secretory program that modulates the tissue microenvironment 1 , 2 . Physiologically, senescence serves as a tumour-suppressive mechanism that prevents the expansion of premalignant cells 3 , 4 and has a beneficial role in wound-healing responses 5 , 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 osteoarthritis 1 , 7 . Accordingly, eliminating senescent cells from damaged tissues in mice ameliorates the symptoms of these pathologies and even promotes longevity 1 , 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.

中文翻译：

---

Senolytic CAR T 细胞逆转衰老相关病理


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 1 , 2 。从生理学角度来看，衰老是一种肿瘤抑制机制，可防止癌前细胞的增殖 3 , 4 ，并在伤口愈合反应中发挥有益作用 5 , 6 。从病理学上讲，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 1 , 7 。因此，消除小鼠受损组织中的衰老细胞可以改善这些病理症状，甚至可以延长寿命 1 , 2 , 8 – 10 。在这里，我们测试了一种治疗概念，即针对衰老细胞的嵌合抗原受体 (CAR) T 细胞可以成为有效的抗衰老剂。我们鉴定出尿激酶型纤溶酶原激活剂受体 (uPAR) 11 是一种在衰老过程中广泛诱导的细胞表面蛋白，并表明 uPAR 特异性 CAR T 细胞可在体外和体内有效消除衰老细胞。靶向 uPAR 的 CAR T 细胞可以延长接受衰老诱导药物组合治疗的肺腺癌小鼠的存活时间，并恢复化学或饮食诱导的肝纤维化小鼠的组织稳态。这些结果确立了抗衰老 CAR T 细胞治疗衰老相关疾病的潜力。嵌合抗原受体 (CAR) T 细胞靶向 uPAR（一种在衰老细胞上上调的细胞表面蛋白），可在体外和体内消除衰老细胞，并减少小鼠的肝纤维化。