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 microenvironment(1,2). Physiologically, senescence serves as a tumor suppressive mechanism that prevents the expansion of premalignant cells(3,4) and plays 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, elimination of senescent cells from damaged tissues in mice ameliorates 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 targeting senescent cells can be effective senolytics. We identify the urokinase plasminogen activator receptor (uPAR)(11) 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.