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ORIGINAL ARTICLES

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

Lin Fan1,2,3,† , Junwei Liu4,5,6,† , Wei Hu4,7,† , Zexin Chen8 , Jie Lan9,10 , Tongtong Zhang4,11 , Yang Zhang1 , Xianpeng Wu1,2 , Zhiwei Zhong1,2 , Danyang Zhang1,2 , Jinlong Zhang1,2 , Rui Qin4,12 , Hui Chen9 , Yunfeng Zong13 , Jianmin Zhang14 , Bing Chen15 , Jun Jiang1,2 , Jifang Cheng1 , Jingyi Zhou14 , Zhiwei Gao15 , Zhenjie Liu15 , Ying Chai16 , Junqiang Fan16 , Pin Wu16 , Yinxuan Chen4 , Yuefeng Zhu17 , Kai Wang18 , Ying Yuan19 , Pintong Huang20 , Ying Zhang20 , Huiqin Feng21 , Kaichen Song5 , Xun Zeng13 , Wei Zhu1,2 , Xinyang Hu1,2,3,* , Weiwei Yin5,22,* , Wei Chen1,2,4,5,12,* , Jian’an Wang1,2,3,*

1Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
2Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, Zhejiang, China
3Research Center for Life Science and Human Health, Binjiang Institute of Zhejiang University, Hangzhou, Zhejiang, China
4Department of Cell Biology, Zhejiang University School of Medicine, and Liangzhu Laboratory, Zhejiang University, Hangzhou, Zhejiang, China
5Key Laboratory for Biomedical Engineering of the Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, Zhejiang, China
6Guangzhou National Laboratory, Guangzhou, Guangdong, China
7Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
8Center of Clinical Epidemiology and Biostatistics and Department of Scientific Research, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
9National Laboratory of Biomacromolecules, Institute of Biophysics, University of Chinese Academy of Sciences, Beijing, China
10Department of Bioinformatics, The Basic Medical School of Chongqing Medical University, Chongqing, China
11Department 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
12The MOE Frontier Science Center for Brain Science & Brainmachine Integration, Zhejiang University, Hangzhou, Zhejiang, China
13National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
14Department of Neurosurgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
15Department of Vascular Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
16Department of Thoracic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
17Department of Vascular Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
18Department of Respiratory, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
19Department of Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
20Department of Ultrasound in Medicine, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
21Department of Clinical Research Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
22Zhejiang Provincial Key Laboratory of Cardio-Cerebral Vascular Detection Technology and Medicinal Effectiveness Appraisal, Zhejiang University, Hangzhou, Zhejiang, China
These authors contributed equally: Lin Fan, Junwei Liu, Wei Hu
* Correspondence: Xinyang Hu(hxy0507@zju.edu.cn)Weiwei Yin(wwyin@zju.edu.cn)Wei Chen(jackweichen@zju.edu.cn)Jian’an Wang(wangjianan111@zju.edu.cn)

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.

https://doi.org/10.1038/s41422-024-00945-0

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