Senolytic CAR T cells reverse senescence-associated pathologies Journal Article
| Authors: | Amor, C.; Feucht, J.; Leibold, J.; Ho, Y. J.; Zhu, C.; Alonso-Curbelo, D.; Mansilla-Soto, J.; Boyer, J. A.; Li, X.; Giavridis, T.; Kulick, A.; Houlihan, S.; Peerschke, E.; Friedman, S. L.; Ponomarev, V.; Piersigilli, A.; Sadelain, M.; Lowe, S. W. |
| Article Title: | Senolytic CAR T cells reverse senescence-associated pathologies |
| Abstract: | 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. © 2020, The Author(s), under exclusive licence to Springer Nature Limited. |
| Keywords: | survival; protein expression; drug efficacy; liver cell carcinoma; nonhuman; mouse; mus; protein targeting; animal experiment; animal model; protein; lung cancer; in vivo study; in vitro study; alanine aminotransferase blood level; aspartate aminotransferase blood level; extracellular matrix; alanine aminotransferase; aspartate aminotransferase; lung adenocarcinoma; antigen; cancer cell; drug response; interleukin 6; chimeric antigen receptor; adoptive transfer; target cell; upregulation; rodent; senescence; liver cell; cytokine release; homeostasis; cell aging; ligand binding; diabetes; concentration response; rna sequence; urokinase receptor; non small cell lung cancer; cell; cytotoxicity test; mitogen activated protein kinase kinase inhibitor; priority journal; article |
| Journal Title: | Nature |
| Volume: | 583 |
| Issue: | 7814 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2020-07-02 |
| Start Page: | 127 |
| End Page: | 132 |
| Language: | English |
| DOI: | 10.1038/s41586-020-2403-9 |
| PUBMED: | 32555459 |
| PROVIDER: | scopus |
| PMCID: | PMC7583560 |
| DOI/URL: | |
| Notes: | Article -- Erratum issued, see DOI: 10.1038/s41586-024-07197-3 -- Export Date: 3 August 2020 -- Source: Scopus |
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