以促炎性 T 细胞为靶点,将其作为一种新的治疗方法,有望解决人类动脉粥样硬化问题

IF 28.1 1区 生物学 Q1 CELL BIOLOGY Cell Research Pub Date : 2024-03-15 DOI:10.1038/s41422-024-00945-0
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
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摘要

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,以控制动脉粥样硬化的发展,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 MACEs,但许多患者仍面临重大风险。强直性脊柱炎进展的另一个关键因素是适应性免疫,但其在预防强直性脊柱炎中的潜在作用仍不清楚。为了研究这个问题,我们对患有强直性脊柱炎斑块的肿瘤患者进行了一项回顾性队列研究。我们发现,抗程序性细胞死亡蛋白1(PD-1)单克隆抗体(mAb)能显著缩小强直性脊柱炎斑块的大小。通过多组学单细胞分析,我们全面描述了强直性脊柱炎斑块特异性PD-1+ T细胞的特征,这些细胞具有激活和促炎作用。我们证明,抗PD-1 mAb被骨髓表达的Fcγ受体(FcγRs)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,在PD-1配体缺乏的强直性脊柱炎斑块中抑制T细胞功能。此外,我们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。我们的分析表明,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。我们的研究表明,T细胞靶向免疫疗法是解决人类强直性脊柱炎的有效策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Targeting pro-inflammatory T cells as a novel therapeutic approach to potentially resolve atherosclerosis in humans
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.
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来源期刊
Cell Research
Cell Research 生物-细胞生物学
CiteScore
53.90
自引率
0.70%
发文量
2420
审稿时长
2.3 months
期刊介绍: Cell Research (CR) is an international journal published by Springer Nature in partnership with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). It focuses on publishing original research articles and reviews in various areas of life sciences, particularly those related to molecular and cell biology. The journal covers a broad range of topics including cell growth, differentiation, and apoptosis; signal transduction; stem cell biology and development; chromatin, epigenetics, and transcription; RNA biology; structural and molecular biology; cancer biology and metabolism; immunity and molecular pathogenesis; molecular and cellular neuroscience; plant molecular and cell biology; and omics, system biology, and synthetic biology. CR is recognized as China's best international journal in life sciences and is part of Springer Nature's prestigious family of Molecular Cell Biology journals.
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