浙江大学王建安等研究人员合作发现，靶向促炎性T细胞可作为一种新的治疗方法来缓解人类动脉粥样硬化。该项研究成果于2024年3月15日在线发表在《细胞研究》杂志上。

研究人员表示，动脉粥样硬化（AS）是导致全球心脑血管疾病的主要原因，其驱动因素是脂质含量的积累和慢性炎症。传统策略主要侧重于降低血脂，以控制AS的发展，但残留的炎症风险会导致重大不良心血管事件（MACE）。虽然针对先天性免疫的抗炎疗法减少了MACE，但许多患者仍面临重大风险。AS进展的另一个关键因素是适应性免疫，但其在预防AS中的潜在作用仍不清楚。

为了研究这个问题，研究人员对患有AS斑块的肿瘤患者进行了一项回顾性队列研究。研究人员发现，抗程序性细胞死亡蛋白1（PD-1）单克隆抗体（mAb）能显著缩小AS斑块的大小。通过多组学单细胞分析，研究人员全面描述了AS斑块特异性PD-1⁺ T细胞的特征，这些细胞具有活化和促炎作用。

研究人员证明，抗PD-1 mAb被骨髓表达的Fcγ受体（FcγR）捕获后，会与T细胞上表达的PD-1相互作用。这种相互作用使抗PD-1 mAb成为PD-1配体的替代物，从而在PD-1配体缺乏的AS斑块中抑制T细胞的功能。此外，研究人员还对使用具有或不具有Fc结合能力的抗PD-1 mAb治疗的肿瘤患者进行了前瞻性队列研究。分析表明，具有Fc结合能力的抗PD-1 mAb能有效缩小AS斑块，而不具有Fc结合能力的抗PD-1 mAb则不能。这些研究表明，T细胞靶向免疫疗法是解决人类AS的有效策略。

附：英文原文

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

Author: 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

Issue&Volume: 2024-03-15

Abstract: 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.

DOI: 10.1038/s41422-024-00945-0

Source: https://www.nature.com/articles/s41422-024-00945-0