Senolytic CAR T cells reverse senescence-associated pathologies.

Area of Science:

• Cellular biology
• Immunotherapy
• Aging research

Background:

• Cellular senescence, a state of stable cell-cycle arrest, plays dual roles in tumor suppression and wound healing.
• Aberrant accumulation of senescent cells drives chronic inflammation and contributes to age-related diseases like fibrosis and osteoarthritis.
• Eliminating senescent cells (senolysis) has shown promise in ameliorating disease symptoms and extending lifespan in preclinical studies.

Purpose of the Study:

• To investigate the therapeutic potential of chimeric antigen receptor (CAR) T cells as senolytic agents.
• To identify a specific target on senescent cells for CAR T cell-mediated elimination.
• To evaluate the efficacy of uPAR-specific CAR T cells in preclinical models of senescence-associated diseases.

Main Methods:

• Identification of cell-surface markers broadly induced on senescent cells.
• Development and characterization of urokinase-type plasminogen activator receptor (uPAR)-specific CAR T cells.
• In vitro and in vivo testing of uPAR-specific CAR T cells for senolytic activity in models of lung adenocarcinoma and liver fibrosis.

Main Results:

• uPAR was identified as a cell-surface protein broadly induced during cellular senescence.
• uPAR-specific CAR T cells demonstrated efficient ablation of senescent cells in vitro and in vivo.
• CAR T cell therapy targeting uPAR extended survival in mice with drug-induced lung adenocarcinoma and restored tissue homeostasis in liver fibrosis models.

Conclusions:

• uPAR is a viable therapeutic target for senescent cells.
• Senolytic CAR T cells targeting uPAR represent a promising therapeutic strategy for senescence-associated diseases.
• This approach holds potential for treating conditions ranging from cancer complications to chronic fibrotic diseases.