Targeting pro-inflammatory T cells as a novel therapeutic approach to potentially resolve atherosclerosis in humans  

作　　者：Lin Fan Junwei Liu Wei Hu Zexin Chen Jie Lan Tongtong Zhang Yang Zhang Xianpeng Wu Zhiwei Zhong Danyang Zhang Jinlong Zhang Rui Qin Hui Chen Yunfeng Zong Jianmin Zhang Bing Chen Jun Jiang Jifang Cheng Jingyi Zhou Zhiwei Gao Zhenjie Liu Ying Chai Junqiang Fan Pin Wu Yinxuan Chen Yuefeng Zhu Kai Wang Ying Yuan Pintong Huang Ying Zhang Huiqin Feng Kaichen Song Xun Zeng Wei Zhu Xinyang Hu Weiwei Yin Wei Chen Jian’an Wang 

机构地区：[1]Department of Cardiology,The Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou,Zhejiang,China [2]Cardiovascular Key Laboratory of Zhejiang Province,Hangzhou,Zhejiang,China [3]Research Center for Life Science and Human Health,Binjiang Institute of Zhejiang University,Hangzhou,Zhejiang,China [4]Department of Cell Biology,Zhejiang University School of Medicine,and Liangzhu Laboratory,Zhejiang University,Hangzhou,Zhejiang,China [5]Key Laboratory for Biomedical Engineering of the Ministry of Education,College of Biomedical Engineering and Instrument Science,Zhejiang University,Hangzhou,Zhejiang,China [6]Guangzhou National Laboratory,Guangzhou,Guangdong,China [7]Kidney Disease Center,The First Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou,Zhejiang,China [8]Center of Clinical Epidemiology and Biostatistics and Department of Scientific Research,The Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou,Zhejiang,China [9]National Laboratory of Biomacromolecules,Institute of Biophysics,University of Chinese Academy of Sciences,Beijing,China [10]Department of Bioinformatics,The Basic Medical School of Chongqing Medical University,Chongqing,China [11]Department of Hepatobiliary and Pancreatic Surgery,The Center for Integrated Oncology and Precision Medicine,Affiliated Hangzhou First People’s Hospital,Zhejiang University School of Medicine,Hangzhou,Zhejiang,China [12]The MOE Frontier Science Center for Brain Science&Brainmachine Integration,Zhejiang University,Hangzhou,Zhejiang,China [13]National Clinical Research Center for Infectious Diseases,The First Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou,Zhejiang,China [14]Department of Neurosurgery,The Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou,Zhejiang,China [15]Department of Vascular Surgery,The Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou,Zhejiang,China [16]Department of Thoracic Surgery,The Second Affiliated Hospital,Zheji

出　　处：《Cell Research》2024年第6期407-427,共21页细胞研究（英文版）

基　　金：supported by the National Key R&D Program of China(2019YFA0110400 to J.A.W.);the National Natural Science Foundation of China(81870292 and 82030014 to J.A.W.,T2394511,92359303,31971237,31470900,and 31522021 to W.C.,82070253 and 82225004 to X.Y.H.,31600751 to W.W.Y.);the Key R&D Projects of Zhejiang Province(2021C03097 to J.A.W.);financial support provided by Binjiang Institute of Zhejiang University(ZY202205SMKY001 for J.A.W.,ZY202205SMKY001 for X.Y.H.);the Ministry of Science and Technology of China(2017ZX10203205 to W.C.);the National Basic Research Program of China(2015CB910800 to W.C.).

摘　　要：Atherosclerosis(AS),a leading cause of cardio-cerebrovascular disease worldwide,is driven by the accumulation of lipid contents and chronic inflammation.Traditional strategies primarily focus on lipid reduction to control AS progression,leaving residual inflammatory risks for major adverse cardiovascular events(MACEs).While anti-inflammatory therapies targeting innate immunity have reduced MACEs,many patients continue to face significant risks.Another key component in AS progression is adaptive immunity,but its potential role in preventing AS remains unclear.To investigate this,we conducted a retrospective cohort study on tumor patients with AS plaques.We found that anti-programmed cell death protein 1(PD-1)monoclonal antibody(mAb)significantly reduces AS plaque size.With multi-omics single-cell analyses,we comprehensively characterized AS plaque-specific PD-1+T cells,which are activated and pro-inflammatory.We demonstrated that anti-PD-1 mAb,when captured by myeloid-expressed Fc gamma receptors(FcγRs),interacts with PD-1 expressed on T cells.This interaction turns the anti-PD-1 mAb into a substitute PD-1 ligand,suppressing T-cell functions in the PD-1 ligands-deficient context of AS plaques.Further,we conducted a prospective cohort study on tumor patients treated with anti-PD-1 mAb with or without Fc-binding capability.Our analysis shows that anti-PD-1 mAb with Fc-binding capability effectively reduces AS plaque size,while anti-PD-1 mAb without Fc-binding capability does not.Our work suggests that T cell-targeting immunotherapy can be an effective strategy to resolve AS in humans.

关 键 词：IMMUNITY INFLAMMATORY RESOLVE 

分 类 号：R730.5[医药卫生—肿瘤]