Targeting senescent cells with NKG2D-CAR T cells

Area of Science:

• Immunology
• Cell Biology
• Gerontology

Background:

• Cellular senescence drives age-related tissue dysfunction and the senescence-associated secretory phenotype (SASP).
• Targeting senescent cells (senolysis) is a therapeutic strategy for aging and related diseases.
• Chimeric antigen receptor (CAR) T cell therapy offers a potential approach for selective senolysis.

Purpose of the Study:

• To investigate the efficacy of NKG2D CAR T cells in eliminating stress-induced senescent cells.
• To evaluate the targeting specificity of NKG2D CAR T cells against senescent cells.
• To explore the potential of NKG2D CAR T cells as a senolytic therapy, particularly for brain aging.

Main Methods:

• Generation and in vitro testing of NKG2D CAR T cells.
• Induction of cellular senescence in mouse embryonic fibroblasts (MEFs) and astrocytes (AST) using genotoxic and oxidative stress.
• Assessment of NKG2D ligand (NKG2DL) expression on senescent cells.
• Evaluation of NKG2D CAR T cell cytotoxicity against senescent and non-senescent cells.

Main Results:

• Genotoxic and oxidative stress induced elevated expression of NKG2DLs on senescent MEFs and AST.
• NKG2D CAR T cells demonstrated potent cytotoxicity against senescent cells.
• NKG2D CAR T cells exhibited minimal toxicity towards non-senescent cells, indicating high specificity.

Conclusions:

• NKG2D CAR T cells effectively target and eliminate stress-induced senescent cells in vitro.
• This study provides the first evidence of NKG2D CAR T cells targeting senescent brain cells.
• NKG2D CAR T cell therapy represents a novel senolytic strategy with potential applications in aging-associated diseases.