Senolytic CAR T cells reverse senescence-associated pathologies

Nature. 2020 Jul;583(7814):127-132. doi: 10.1038/s41586-020-2403-9. Epub 2020 Jun 17.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / immunology
  • Adenocarcinoma / pathology
  • Adenocarcinoma / therapy
  • Aging / pathology*
  • Animals
  • Carbon Tetrachloride
  • Cellular Senescence / immunology*
  • Female
  • Heterografts
  • Humans
  • Liver Cirrhosis / chemically induced
  • Liver Cirrhosis / immunology
  • Liver Cirrhosis / pathology
  • Liver Cirrhosis / therapy*
  • Longevity / immunology*
  • Lung Neoplasms / immunology
  • Lung Neoplasms / pathology
  • Lung Neoplasms / therapy*
  • Male
  • Mice
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Receptors, Chimeric Antigen / immunology*
  • Receptors, Chimeric Antigen / metabolism
  • Receptors, Urokinase Plasminogen Activator / genetics
  • Receptors, Urokinase Plasminogen Activator / metabolism
  • Rejuvenation*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / metabolism

Substances

  • Receptors, Cell Surface
  • Receptors, Chimeric Antigen
  • Receptors, Urokinase Plasminogen Activator
  • Carbon Tetrachloride