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Targeting senescent cells with NKG2D-CAR T cells

Deng, Yushuang, Kumar, Avadh, Xie, Kan, Schaaf, Kristina, Scifo, Enzo, Morsy, Sarah, Li, Tao, Ehninger, Armin, Bano, Daniele, Ehninger, Dan·2024·Cell Death Discovery
DOI 10.1038/s41420-024-01976-7PMC PMC11069534
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Abstract

This study investigates the efficacy of NKG2D chimeric antigen receptor (CAR) engineered T cells in targeting and eliminating stress-induced senescent cells in vitro. Cellular senescence contributes to age-related tissue decline and is characterized by permanent cell cycle arrest and the senescence-associated secretory phenotype (SASP). Immunotherapy, particularly CAR-T cell therapy, emerges as a promising approach to selectively eliminate senescent cells. Our focus is on the NKG2D receptor, which binds to ligands (NKG2DLs) upregulated in senescent cells, offering a target for CAR-T cells. Using mouse embryonic fibroblasts (MEFs) and astrocytes (AST) as senescence models, we demonstrate the elevated expression of NKG2DLs in response to genotoxic and oxidative stress. NKG2D-CAR T cells displayed potent cytotoxicity against these senescent cells, with minimal effects on non-senescent cells, suggesting their potential as targeted senolytics. In conclusion, our research presents the first evidence of NKG2D-CAR T cells’ ability to target senescent brain cells, offering a novel approach to manage senescence-associated diseases. The findings pave the way for future investigations into the therapeutic applicability of NKG2D-targeting CAR-T cells in naturally aged organisms and models of aging-associated brain diseases in vivo.

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Metadata

Authors
Deng, Y., Kumar, A., Xie, K., Schaaf, K., Scifo, E., Morsy, S., Li, T., Ehninger, A., Bano, D., & Ehninger, D.
Venue
Cell Death Discovery
Publisher
Springer Science and Business Media LLC
Published
2024-05-04
Volume
10
Issue
1
ISSN
2058-7716
DOI
10.1038/s41420-024-01976-7
PMC
PMC11069534
Cited by
75
References
28
Language
en
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