TY - JOUR
T1 - Senolytic CAR T cells reverse senescence-associated pathologies
AU - Amor, Corina
AU - Feucht, Judith
AU - Leibold, Josef
AU - Ho, Yu Jui
AU - Zhu, Changyu
AU - Alonso-Curbelo, Direna
AU - Mansilla-Soto, Jorge
AU - Boyer, Jacob A.
AU - Li, Xiang
AU - Giavridis, Theodoros
AU - Kulick, Amanda
AU - Houlihan, Shauna
AU - Peerschke, Ellinor
AU - Friedman, Scott L.
AU - Ponomarev, Vladimir
AU - Piersigilli, Alessandra
AU - Sadelain, Michel
AU - Lowe, Scott W.
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/7/2
Y1 - 2020/7/2
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85086711328&partnerID=8YFLogxK
U2 - 10.1038/s41586-020-2403-9
DO - 10.1038/s41586-020-2403-9
M3 - Article
C2 - 32555459
AN - SCOPUS:85086711328
SN - 0028-0836
VL - 583
SP - 127
EP - 132
JO - Nature
JF - Nature
IS - 7814
ER -