Faculty Opinions recommendation of Senolytic CAR T cells reverse senescence-associated pathologies.
2020-07-11

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][9][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.Given the contribution of senescence to tissue damage, there is growing interest in the development of 'senolytic' agents that selectively eliminate senescent cells 12 .Several small molecules display such activity, but most lack potency and produce substantial side effects 1,12,13 .An alternative approach could involve CAR T cells directed against senescence-specific surface antigens.CARs are synthetic receptors that redirect T cell specificity, effector potential and other functions 14 .CAR T cells targeting CD19 have shown remarkable efficacy in patients with refractory B-cell malignancies 15 and other cell-surface antigens show promise as targets for CAR therapy in other indications [16][17][18] .Here we investigate whether CAR T cells could serve as senolytic agents.To identify cell surface proteins that are broadly and specifically upregulated in senescent cells, we compared RNAseq datasets derived from three independent and robust models of senescence: 1) Therapy-induced senescence (TIS) in murine lung adenocarcinoma Kras G12D ;p53 -/-(KP) cells triggered to senesce by the combination of MEK and CDK4/6 inhibitors 19 ; 2) Oncogene-induced senescence (OIS) in murine hepatocytes mediated by in vivo delivery of NRAS G12V through hydrodynamic tail vein injection (HTVI) 4 ; and 3) Culture-induced senescence of murine hepatic stellate cells (HSCs) (Extended Data Fig. 1a).We focused on transcripts encoding molecules located in the plasma membrane as determined by UniProtKB that were upregulated in all datasets (Extended Data Fig. 1b,c).8 transcripts were identified, each encoding proteins linked to extracellular matrix remodeling or the coagulation cascade (Extended Data Fig. 1 d).Given that ideal antigens for CAR T cell engagement should be highly expressed on target cells but not vital tissues, we ranked each transcript according to its magnitude of upregulation (log 2 fold change), and then excluded those highly expressed in vital tissues as determined by the Human Protein Atlas (HPA) and Human Proteome Map (HPM) 20 .