IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v583y2020i7814d10.1038_s41586-020-2403-9.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41586-020-2403-9
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.

    File URL: https://libkey.io/10.1038/s41586-020-2403-9?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. 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.
    2. 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.
    3. 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.
    4. 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.
    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.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:583:y:2020:i:7814:d:10.1038_s41586-020-2403-9. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.