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

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

作者地址："[Fan, Lin; Zhang, Yang; Wu, Xianpeng; Zhong, Zhiwei; Zhang, Danyang; Zhang, Jinlong; Jiang, Jun; Cheng, Jifang; Zhu, Wei; Hu, Xinyang; Chen, Wei; Wang, Jianan] Zhejiang Univ, Affiliated Hosp 2, Dept Cardiol, Sch Med, Hangzhou, Zhejiang, Peoples R China; [Fan, Lin; Wu, Xianpeng; Zhong, Zhiwei; Zhang, Danyang; Zhang, Jinlong; Jiang, Jun; Zhu, Wei; Hu, Xinyang; Chen, Wei; Wang, Jianan] Cardiovasc Key Lab Zhejiang Prov, Hangzhou, Zhejiang, Peoples R China; [Fan, Lin; Hu, Xinyang; Wang, Jianan] Zhejiang Univ, Res Ctr Life Sci & Human Hlth, Binjiang Inst, Hangzhou, Zhejiang, Peoples R China; [Liu, Junwei; Hu, Wei; Zhang, Tongtong; Qin, Rui; Chen, Yinxuan; Chen, Wei] Zhejiang Univ, Sch Med, Dept Cell Biol, Liangzhu Lab, Hangzhou, Zhejiang, Peoples R China; [Liu, Junwei; Song, Kaichen; Yin, Weiwei; Chen, Wei] Zhejiang Univ, Coll Biomed Engn & Instrument Sci, Key Lab Biomed Engn Minist Educ, Minist Educ, Hangzhou, Zhejiang, Peoples R China; [Liu, Junwei] Guangzhou Natl Lab, Guangzhou, Guangdong, Peoples R China; [Hu, Wei] Zhejiang Univ, Affiliated Hosp 1, Kidney Dis Ctr, Sch Med, Hangzhou, Zhejiang, Peoples R China; [Chen, Zexin] Zhejiang Univ, Affiliated Hosp 2,Sch Med, Ctr Clin Epidemiol & Biostat, Dept Sci Res, Hangzhou, Zhejiang, Peoples R China; [Lan, Jie; Chen, Hui] Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromolecules, Beijing, Peoples R China; [Lan, Jie] Chongqing Med Univ, Dept Bioinformat, Basic Med Sch, Chongqing, Peoples R China; [Zhang, Tongtong] Zhejiang Univ, Affiliated Hangzhou Peoples Hosp 1, Ctr Integrated Oncol & Precis Med,Sch Med, Dept Hepatobiliary & Pancreat Surg, Hangzhou, Zhejiang, Peoples R China; [Qin, Rui; Chen, Wei] Zhejiang Univ, MOE Frontier Sci Ctr Brain Sci & Brain machine Int, Hangzhou, Zhejiang, Peoples R China; [Zong, Yunfeng; Zeng, Xun] Zhejiang Univ, Affiliated Hosp 1, Sch Med, Hangzhou, Zhejiang, Peoples R China; [Zhang, Jianmin; Zhou, Jingyi] Zhejiang Univ, Affiliated Hosp 2, Sch Med, Hangzhou, Zhejiang, Peoples R China; [Chen, Bing; Gao, Zhiwei; Liu, Zhenjie] Zhejiang Univ, Affiliated Hosp 2, Dept Vasc Surg, Sch Med, Hangzhou, Zhejiang, Peoples R China; [Chai, Ying; Fan, Junqiang; Wu, Pin] Zhejiang Univ, Affiliated Hosp 2, Sch Med, Hangzhou, Zhejiang, Peoples R China; [Zhu, Yuefeng] Zhejiang Univ, Sir Run Run Shaw Hosp, Dept Vasc Surg, Sch Med, Hangzhou, Zhejiang, Peoples R China; [Wang, Kai] Zhejiang Univ, Affiliated Hosp 2, Dept Resp, Sch Med, Hangzhou, Zhejiang, Peoples R China; [Yuan, Ying] Zhejiang Univ, Affiliated Hosp 2, Dept Oncol, Sch Med, Hangzhou, Zhejiang, Peoples R China; [Huang, Pintong; Zhang, Ying] Zhejiang Univ, Affiliated Hosp 2, Dept Ultrasound Med, Sch Med, Hangzhou, Zhejiang, Peoples R China; [Feng, Huiqin] Zhejiang Univ, Affiliated Hosp 2, Sch Med, Dept Clin Res Ctr, Hangzhou, Zhejiang, Peoples R China; [Yin, Weiwei] Zhejiang Univ, Zhejiang Prov Key Lab Cardiocerebral Vasc Detect T, Hangzhou, Zhejiang, Peoples R China"

通信作者："Hu, XY; Chen, W; Wang, JA (通讯作者)，Zhejiang Univ, Affiliated Hosp 2, Dept Cardiol, Sch Med, Hangzhou, Zhejiang, Peoples R China.; Hu, XY; Chen, W; Wang, JA (通讯作者)，Cardiovasc Key Lab Zhejiang Prov, Hangzhou, Zhejiang, Peoples R China.; Hu, XY; Wang, JA (通讯作者)，Zhejiang Univ, Res Ctr Life Sci & Human Hlth, Binjiang Inst, Hangzhou, Zhejiang, Peoples R China.; Chen, W (通讯作者)，Zhejiang Univ, Sch Med, Dept Cell Biol, Liangzhu Lab, Hangzhou, Zhejiang, Peoples R China.; Yin, WW; Chen, W (通讯作者)，Zhejiang Univ, Coll Biomed Engn & Instrument Sci, Key Lab Biomed Engn Minist Educ, Minist Educ, Hangzhou, Zhejiang, Peoples R China.; Chen, W (通讯作者)，Zhejiang Univ, MOE Frontier Sci Ctr Brain Sci & Brain machine Int, Hangzhou, Zhejiang, Peoples R China.; Yin, WW (通讯作者)，Zhejiang Univ, Zhejiang Prov Key Lab Cardiocerebral Vasc Detect T, Hangzhou, Zhejiang, Peoples R China."

来源：CELL RESEARCH

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001185853500002

JCR分区：Q1

影响因子：28.1

年份：2024

卷号：34

期号：4

开始页：331

结束页：331

文献类型：Article

关键词：　

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 (Fc gamma Rs), 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."

基金机构："Ministry of Science and Technology of the People's Republic of China (Chinese Ministry of Science and Technology) [2019YFA0110400]; National Key R&D Program of China [81870292, 82030014, T2394511, 92359303, 31971237, 31470900, 31522021, 82070253, 82225004, 31600751]; National Natural Science Foundation of China [2021C03097]; Key R&D Projects of Zhejiang Province [ZY202205SMKY001]; Binjiang Institute of Zhejiang University [2017ZX10203205]; Ministry of Science and Technology of China [2015CB910800]; National Basic Research Program of China"

基金资助正文："We greatly appreciate all study participants for their generous donations of blood, AS plaque, and lung tumor samples, and the clinical staff at SAHZU for their help with sample collection. We also extend our gratitude to T. Zhang from BeiGene for kindly providing us with CD64+ HEK293 cells, and J. Lou from the University of Chinese Academy of Sciences for kindly providing us with Jurkat T cells. We thank PLT Tech for single-cell sample preparation and CyTOF service, Novogene for scRNA-seq and scTCR-seq, LC-BIO for snATAC-seq, and Hangzhou Leading Pharmatech for their flow cytometry service. We appreciate T. Wang, and C. Qiu for their help with sample preparation, and Q. Tao and Y. Zhao for their assistance. We thank C. Dong, H. Qi, L. Lu, J. Wang, J. Lou, C. Liu, H. Shi, and Q. Ji for their discussion and technical support. This study was 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.), and 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.), and the National Basic Research Program of China (2015CB910800 to W.C.)."