Senolytic CAR T cells reverse senescence-associated pathologies
By Corina Amor, J. Feucht, J. Leibold, Yu-jui Ho, Changyu Zhu, Direna Alonso-Curbelo, J. Mansilla-Soto, Jacob A Boyer, Xiang Li, Theodoros Giavridis and 8 more. Nature, 2020
956 citations recorded by the source corpus.
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. Chimeric antigen receptor (CAR) T cells targeting uPAR, a cell-surface protein that is upregulated on senescent cells, eliminate senescent cells in vitro and in vivo and reduce liver fibrosis in mice.
Subfields: Immunology, Molecular Biology, Oncology
View Paper: https://www.semanticscholar.org/paper/04e18a651e78de49d44a74b1db3d968208b4c3a1
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Citations in the corpus
- Immunosenescence: molecular mechanisms and diseases (2023, background): “uPAR-specific CAR T cells could effectively eliminate senescent cells in mice, although further investigations are required to explore whether they have the necessary safety profile for clinical application.(203) Despite this caveat, there is growing interest in identifying novel markers of senescen”
- Inflammation and aging: signaling pathways and intervention therapies (2023, background): “It was found that anti-uPAR-CAR-T cells were effective in removing senescent cells in vitro and precancerous and malignant cells in mouse models of liver and lung in the presence of potentially toxic.(350) Previously, CAR-T therapy targeting FAP was found to significantly reduce cardiac fibrosis and”
- Senescence and the SASP: many therapeutic avenues (2020, background): “Rather than using senolytics, Amor et al. (2020) engineered chimeric antigen receptor (CAR) T cells recognizing uPAR, a protein expressed by senescent cells, a strategy that mirrors normal senescence immunosurveillance.”