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Senolytic CAR T cells reverse senescence-associated pathologies

Author

Listed:
  • Corina Amor

    (Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Judith Feucht

    (Center for Cell Engineering, Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Josef Leibold

    (Memorial Sloan Kettering Cancer Center)

  • Yu-Jui Ho

    (Memorial Sloan Kettering Cancer Center)

  • Changyu Zhu

    (Memorial Sloan Kettering Cancer Center)

  • Direna Alonso-Curbelo

    (Memorial Sloan Kettering Cancer Center)

  • Jorge Mansilla-Soto

    (Center for Cell Engineering, Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Jacob A. Boyer

    (Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Xiang Li

    (Memorial Sloan Kettering Cancer Center
    Weill Cornell Graduate School of Medical Sciences)

  • Theodoros Giavridis

    (Center for Cell Engineering, Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Amanda Kulick

    (Memorial Sloan Kettering Cancer Center)

  • Shauna Houlihan

    (Memorial Sloan Kettering Cancer Center)

  • Ellinor Peerschke

    (Memorial Sloan Kettering Cancer Center)

  • Scott L. Friedman

    (Icahn School of Medicine at Mount Sinai)

  • Vladimir Ponomarev

    (Memorial Sloan Kettering Cancer Center)

  • Alessandra Piersigilli

    (Rockefeller University, Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center)

  • Michel Sadelain

    (Center for Cell Engineering, Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Scott W. Lowe

    (Memorial Sloan Kettering Cancer Center
    Howard Hughes Medical Institute)

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.

Suggested Citation

  • 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 , 2020. "Senolytic CAR T cells reverse senescence-associated pathologies," Nature, Nature, vol. 583(7814), pages 127-132, July.
  • Handle: RePEc:nat:nature:v:583:y:2020:i:7814:d:10.1038_s41586-020-2403-9
    DOI: 10.1038/s41586-020-2403-9
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    Citations

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    Cited by:

    1. Shujuan Yu & Yaqun Sui & Jiawei Wang & Yongdong Li & Hanlin Li & Yingping Cao & Liqing Chen & Longguang Jiang & Cai Yuan & Mingdong Huang, 2022. "Crystal structure and cellular functions of uPAR dimer," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Imanol Duran & Joaquim Pombo & Bin Sun & Suchira Gallage & Hiromi Kudo & Domhnall McHugh & Laura Bousset & Jose Efren Barragan Avila & Roberta Forlano & Pinelopi Manousou & Mathias Heikenwalder & Domi, 2024. "Detection of senescence using machine learning algorithms based on nuclear features," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    3. Madison L. Doolittle & Dominik Saul & Japneet Kaur & Jennifer L. Rowsey & Stephanie J. Vos & Kevin D. Pavelko & Joshua N. Farr & David G. Monroe & Sundeep Khosla, 2023. "Multiparametric senescent cell phenotyping reveals targets of senolytic therapy in the aged murine skeleton," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    4. Toshiyuki Ko & Seitaro Nomura & Shintaro Yamada & Kanna Fujita & Takanori Fujita & Masahiro Satoh & Chio Oka & Manami Katoh & Masamichi Ito & Mikako Katagiri & Tatsuro Sassa & Bo Zhang & Satoshi Hatsu, 2022. "Cardiac fibroblasts regulate the development of heart failure via Htra3-TGF-β-IGFBP7 axis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    5. Rana Salam & Alexa Saliou & Franck Bielle & Mathilde Bertrand & Christophe Antoniewski & Catherine Carpentier & Agusti Alentorn & Laurent Capelle & Marc Sanson & Emmanuelle Huillard & Léa Bellenger & , 2023. "Cellular senescence in malignant cells promotes tumor progression in mouse and patient Glioblastoma," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    6. Hongwei Yao & Joselynn Wallace & Abigail L. Peterson & Alejandro Scaffa & Salu Rizal & Katy Hegarty & Hajime Maeda & Jason L. Chang & Nathalie Oulhen & Jill A. Kreiling & Kelsey E. Huntington & Moniqu, 2023. "Timing and cell specificity of senescence drives postnatal lung development and injury," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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