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Updated: Jul 19, 2025
Advances in Human Induced Pluripotent Stem Cell-Derived Chimeric Antigen Receptor-Expressing Natural Killer Cells
Published on: February 14, 2025
NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates
Dong Yang1, Bin Sun1, Shirong Li1
1Department of Targeting Therapy and Immunology and Laboratory of Animal Tumor Models, Cancer Center and State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics and Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
Abstract:
Cellular senescence, characterized by stable cell cycle arrest, plays an important role in aging and age-associated pathologies. Eliminating senescent cells rejuvenates aged tissues and ameliorates age-associated diseases. Here, we identified that natural killer group 2 member D ligands (NKG2DLs) are up-regulated in senescent cells in vitro, regardless of stimuli that induced cellular senescence, and in various tissues of aged mice and nonhuman primates in vivo. Accordingly, we developed and demonstrated that chimeric antigen receptor (CAR) T cells targeting human NKG2DLs selectively and effectively diminish human cells undergoing senescence induced by oncogenic stress, replicative stress, DNA damage, or P16INK4a overexpression in vitro. Targeting senescent cells with mouse NKG2D-CAR T cells alleviated multiple aging-associated pathologies and improved physical performance in both irradiated and aged mice. Autologous T cells armed with the human NKG2D CAR effectively delete naturally occurring senescent cells in aged nonhuman primates without any observed adverse effects. Our findings establish that NKG2D-CAR T cells could serve as potent and selective senolytic agents for aging and age-associated diseases driven by senescence.
Insights
Natural killer group 2 member D ligands (NKG2DLs) are upregulated in senescent cells. Chimeric antigen receptor (CAR) T cells targeting NKG2DLs effectively eliminate senescent cells, rejuvenating tissues and treating age-associated diseases.
Area of Science:
- Gerontology and Immunology
- Cellular Biology and Aging Research
Background:
- Cellular senescence, a state of stable cell cycle arrest, is implicated in aging and age-related diseases.
- Eliminating senescent cells has shown potential in rejuvenating tissues and mitigating age-associated pathologies.
Purpose of the Study:
- To investigate the role of natural killer group 2 member D ligands (NKG2DLs) in cellular senescence.
- To develop and evaluate chimeric antigen receptor (CAR) T cells targeting NKG2DLs as a senolytic therapy.
Main Methods:
- Identification of NKG2DLs upregulation in senescent cells across various induction methods and in vivo models (aged mice, nonhuman primates).
- Development of NKG2D-CAR T cells targeting human NKG2DLs for selective elimination of senescent cells.
- In vitro and in vivo testing of CAR T cells in models of senescence and aging.
Main Results:
- NKG2DLs were consistently upregulated in senescent cells, irrespective of the senescence-inducing stimulus.
- NKG2D-CAR T cells demonstrated selective and effective elimination of senescent cells in vitro.
- Treatment with NKG2D-CAR T cells in mice ameliorated aging pathologies and improved physical function.
- Autologous NKG2D CAR T cells safely cleared naturally occurring senescent cells in aged nonhuman primates.
Conclusions:
- NKG2DLs are a reliable marker for senescent cells.
- NKG2D-CAR T cells represent a promising and selective senolytic therapy.
- This approach holds potential for treating aging and senescence-driven diseases.
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