Amor, Corina, Feucht, Judith, Leibold, Josef, Ho, Yu-Jui, Zhu, Changyu, Alonso-Curbelo, Direna, Mansilla-Soto, Jorge, Boyer, Jacob A, Li, Xiang, Giavridis, Theodoros, Kulick, Amanda, Houlihan, Shauna, Peerschke, Ellinor, Friedman, Scott L, Ponomarev, Vladimir, Piersigilli, Alessandra, Sadelain, Michel, Lowe, Scott W (July 2020) Senolytic CAR T cells reverse senescence-associated pathologies. Nature, 583 (7814). pp. 127-132. ISSN 1476-4687
Abstract
Cellular senescence is characterized by stable cell-cycle arrest and a secretory program that modulates the tissue microenvironment. Physiologically, senescence serves as a tumour-suppressive mechanism that prevents the expansion of premalignant cells and has 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, eliminating senescent cells from damaged tissues in mice ameliorates the symptoms of these pathologies and even promotes longevity. 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) 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.
| Item Type: | Paper |
|---|---|
| Subjects: | organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell cycle organs, tissues, organelles, cell types and functions > cell types and functions > cell types > immune cell organs, tissues, organelles, cell types and functions > cell types and functions > cell types > immune cell organs, tissues, organelles, cell types and functions > cell types and functions > cell types > immune cell organs, tissues, organelles, cell types and functions > organs types and functions > liver diseases & disorders > cancer > cancer types > lung cancer organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > senescence |
| CSHL Authors: | |
| Communities: | CSHL labs > Amor lab |
| Depositing User: | Sasha Luks-Morgan |
| Date: | 17 July 2020 |
| Date Deposited: | 17 Sep 2021 20:04 |
| Last Modified: | 19 Aug 2024 14:38 |
| PMCID: | PMC7583560 |
| URI: | https://repository.cshl.edu/id/eprint/40353 |
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