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ORIGINAL ARTICLES

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

Lin Fan^1,2,3,† , Junwei Liu^4,5,6,† , Wei Hu^4,7,† , Zexin Chen⁸ , Jie Lan^9,10 , Tongtong Zhang^4,11 , Yang Zhang¹ , Xianpeng Wu^1,2 , Zhiwei Zhong^1,2 , Danyang Zhang^1,2 , Jinlong Zhang^1,2 , Rui Qin^4,12 , Hui Chen⁹ , Yunfeng Zong¹³ , Jianmin Zhang¹⁴ , Bing Chen¹⁵ , Jun Jiang^1,2 , 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 Zhu^1,2 , Xinyang Hu^1,2,3,* , Weiwei Yin^5,22,* , Wei Chen^1,2,4,5,12,* , Jian’an Wang^1,2,3,*

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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