Senolytic CAR T cells reverse senescence-associated pathologies

Corina Amor, Judith Feucht, Josef Leibold, Yu Jui Ho, Changyu Zhu, Direna Alonso-Curbelo, Jorge Mansilla-Soto, Jacob A. Boyer, Xiang Li, Theodoros Giavridis, Amanda Kulick, Shauna Houlihan, Ellinor Peerschke, Scott L. Friedman, Vladimir Ponomarev, Alessandra Piersigilli, Michel Sadelain, Scott W. Lowe

Research output: Contribution to journalArticlepeer-review

251 Scopus citations

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.

Original languageEnglish
Pages (from-to)127-132
Number of pages6
JournalNature
Volume583
Issue number7814
DOIs
StatePublished - 2 Jul 2020

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