Visualizing Immune Checkpoint Inhibitors Derived Inflammation in Atherosclerosis.

IF 16.5 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Circulation research Pub Date : 2024-09-27 DOI:10.1161/circresaha.124.324260

Lanlan Lou,Lisa Detering,Hannah Luehmann,Junedh M Amrute,Deborah Sultan,Pan Ma,Alexandria Li,Divangana Lahad,Andreas Bredemeyer,Xiuli Zhang,Gyu Seong Heo,Kory Lavine,Yongjian Liu

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引用次数: 0

Abstract

BACKGROUND Immune checkpoint inhibitor (ICI) usage has resulted in immune-related adverse events in patients with cancer, such as accelerated atherosclerosis. Of immune cells involved in atherosclerosis, the role of CCR2+ (CC motif chemokine receptor 2-positive) proinflammatory macrophages is well documented. However, there is no noninvasive approach to determine the changes of these cells in vivo following ICI treatment and explore the underlying mechanisms of immune-related adverse events. Herein, we aim to use a CCR2 (CC motif chemokine receptor 2)-targeted radiotracer and positron emission tomography (PET) to assess the aggravated inflammatory response caused by ICI treatment in mouse atherosclerosis models and explore the mechanism of immune-related adverse events. METHODS Apoe-/- mice and Ldlr-/- mice were treated with an ICI, anti-PD1 (programmed cell death protein 1) antibody, and compared with those injected with either isotype control IgG or saline. The radiotracer 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-ECL1i (extracellular loop 1 inverso) was used for PET imaging of CCR2+ macrophages. Atherosclerotic arteries were collected for molecular characterization. RESULTS CCR2 PET revealed significantly higher radiotracer uptake in both Apoe-/- and Ldlr-/- mice treated with anti-PD1 compared with the control groups. The increased expression of CCR2+ cells in Apoe-/- and Ldlr-/- mice was confirmed by immunostaining and flow cytometry. Single-cell RNA sequencing revealed elevated expression of CCR2 in myeloid cells. Mechanistically, IFNγ (interferon gamma) was essential for aggravated inflammation and atherosclerotic plaque progression following anti-PD1 treatment. CONCLUSIONS Accelerated atherosclerotic plaque inflammation triggered by anti-PD1 treatment can be noninvasively detected by 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-ECL1i PET. Aggravated plaque inflammation is time- and dose-dependent and predominately mediated by IFNγ signaling. This study warrants further investigation of CCR2 PET as a noninvasive approach to visualize atherosclerotic plaque inflammation and explore the underlying mechanism following ICI treatment.

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可视化动脉粥样硬化中由免疫检查点抑制剂引发的炎症。

背景免疫检查点抑制剂（ICI）的使用导致癌症患者出现免疫相关不良事件，如加速动脉粥样硬化。在参与动脉粥样硬化的免疫细胞中，CCR2+（CC motif 趋化因子受体 2 阳性）促炎性巨噬细胞的作用已得到充分证实。然而，目前还没有非侵入性方法来确定 ICI 治疗后这些细胞在体内的变化，并探索免疫相关不良事件的潜在机制。方法用CCR2（CC motif趋化因子受体2）靶向放射性示踪剂和正电子发射断层扫描（PET）评估ICI治疗在小鼠动脉粥样硬化模型中引起的加重的炎症反应，并探索免疫相关不良事件的机制。放射性示踪剂 1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸-ECL1i（细胞外环路 1 inverso）用于 CCR2+ 巨噬细胞的 PET 成像。结果CCR2 PET显示，与对照组相比，接受抗PD1治疗的载脂蛋白/-小鼠和Ldlr-/-小鼠的放射性示踪剂摄取量明显增加。免疫染色法和流式细胞术证实载脂蛋白-/-小鼠和低密度脂蛋白-/-小鼠的 CCR2+ 细胞表达增加。单细胞 RNA 测序显示髓系细胞中 CCR2 的表达升高。结论1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸-ECL1i PET可以无创检测抗PD1治疗引发的动脉粥样硬化斑块炎症。斑块炎症加重具有时间和剂量依赖性，主要由 IFNγ 信号传导介导。这项研究值得进一步研究 CCR2 PET，将其作为一种非侵入性方法来观察动脉粥样硬化斑块炎症并探索 ICI 治疗后的潜在机制。

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来源期刊

Circulation research 医学-外周血管病

CiteScore

29.60

自引率

2.00%

发文量

535

审稿时长

3-6 weeks

期刊介绍： Circulation Research is a peer-reviewed journal that serves as a forum for the highest quality research in basic cardiovascular biology. The journal publishes studies that utilize state-of-the-art approaches to investigate mechanisms of human disease, as well as translational and clinical research that provide fundamental insights into the basis of disease and the mechanism of therapies. Circulation Research has a broad audience that includes clinical and academic cardiologists, basic cardiovascular scientists, physiologists, cellular and molecular biologists, and cardiovascular pharmacologists. The journal aims to advance the understanding of cardiovascular biology and disease by disseminating cutting-edge research to these diverse communities. In terms of indexing, Circulation Research is included in several prominent scientific databases, including BIOSIS, CAB Abstracts, Chemical Abstracts, Current Contents, EMBASE, and MEDLINE. This ensures that the journal's articles are easily discoverable and accessible to researchers in the field. Overall, Circulation Research is a reputable publication that attracts high-quality research and provides a platform for the dissemination of important findings in basic cardiovascular biology and its translational and clinical applications.