机构:[1]Department 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.四川大学华西医院[2]Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming,, Yunnan 650223, China.[3]Department of Urology, Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
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.
基金:
This work wassupported by
National Natural Science Foundation of China grant U1702289 and 82172701 (to X. Zhao);
National Key R&D Program of China grant 2018YFC200043 (to X. Zhao); 1.3.5 Project for
Disciplines of Excellence, West China Hospital, Sichuan University grant ZYYC20002 (to X. Zhao);
and Department of Science and Technology of Sichuan Province grant 2020JDRC0019 (to D.Y.).
语种:
外文
PubmedID:
中科院(CAS)分区:
出版当年[2023]版:
大类|1 区医学
小类|1 区细胞生物学1 区医学:研究与实验
最新[2025]版:
大类|1 区医学
小类|1 区细胞生物学1 区医学:研究与实验
第一作者:
第一作者机构:[1]Department 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.
共同第一作者:
通讯作者:
通讯机构:[1]Department 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.[2]Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming,, Yunnan 650223, China.
推荐引用方式(GB/T 7714):
Yang Dong,Sun Bin,Li Shirong,et al.NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates[J].Science translational medicine.2023,15(709):eadd1951.doi:10.1126/scitranslmed.add1951.
APA:
Yang Dong,Sun Bin,Li Shirong,Wei Wenwen,Liu Xiuyun...&Zhao Xudong.(2023).NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates.Science translational medicine,15,(709)
MLA:
Yang Dong,et al."NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates".Science translational medicine 15..709(2023):eadd1951