This study utilized CCR2 PET imaging to demonstrate the inflammatory changes induced by PD-1 antibody therapy in atherosclerosis models and explored the critical role of IFNγ in this process.
Literature Overview
The article, 'Visualizing Immune Checkpoint Inhibitors Derived Inflammation in Atherosclerosis', published in Circulation Research, reviews the impact of immune checkpoint inhibitors (ICIs) on atherosclerosis, particularly mechanisms by which PD-1 antibody therapy intensifies inflammatory responses. The work systematically analyzed alterations in CCR2+ monocytes/macrophages within atherosclerotic plaques and validated 64Cu-DOTA-ECL1i PET imaging as a non-invasive tool to assess inflammation status post-ICI treatment. Additionally, scRNA-seq and flow cytometry techniques revealed the central role of IFNγ signaling in ICI-exacerbated inflammation. End of paragraph
Background Knowledge
Atherosclerosis is a chronic inflammatory disease closely linked to immune cell infiltration and activation, particularly pro-inflammatory monocytes/macrophages. While ICIs like PD-1 antibodies have revolutionized cancer therapy, their immune-related adverse events (irAEs), especially cardiovascular effects, are increasingly recognized. Existing studies suggest ICIs may accelerate plaque inflammation by activating T cells and enhancing IFNγ expression. However, non-invasive tools for real-time monitoring of ICI-induced inflammatory changes in atherosclerosis remain lacking. This study fills this gap by developing and validating 64Cu-DOTA-ECL1i as a specific PET tracer for CCR2+ cells to detect inflammation dynamics in mouse models post-ICI treatment. It further elucidates the non-cell-autonomous role of IFNγ in ICI-mediated inflammation, providing a foundation for therapeutic strategies targeting CCR2 or IFNγ. End of paragraph
Research Methods and Experiments
Apoe−/− and Ldlr−/− mice were employed as atherosclerosis models. PD-1 antibody (10 mg/kg) was administered via intraperitoneal injection twice weekly to simulate ICI treatment, with control groups receiving isotype-matched IgG or saline. CCR2+ monocyte/macrophage enrichment in the aortic arch was evaluated using 64Cu-DOTA-ECL1i PET/CT imaging, validated through histopathology (H&E, Oil Red O staining), flow cytometry, and quantitative RT-PCR. scRNA-seq analyzed gene expression shifts in immune cell subsets, while intervention experiments with IFNγ or CD8 antibodies assessed inflammation mitigation.
Key Conclusions and Perspectives
Research Significance and Prospects
This work provides a non-invasive imaging strategy for monitoring ICI-induced atherosclerotic inflammation in cancer patients and identifies novel therapeutic targets for mitigating irAEs. Future studies should validate the clinical applicability of CCR2 PET imaging in humanized models and assess the translational potential of IFNγ-blocking approaches.
Conclusion
This study systematically evaluated the inflammatory effects of PD-1 antibody therapy in murine atherosclerosis models, establishing CCR2 PET as a non-invasive detection method. PD-1 inhibition significantly increased CCR2+ monocyte/macrophage infiltration through IFNγ signaling, exacerbating plaque inflammation. Interventions with IFNγ or CD8 antibodies effectively mitigated inflammatory responses, demonstrating their potential as therapeutic targets. Notably, ICI effects exhibited time- and dose-dependency, persisting for weeks post-treatment. These findings offer critical insights for monitoring and managing ICI-related cardiovascular irAEs, paving the way for clinical translation and personalized therapeutic strategies. The imaging approach may enable individualized inflammation assessment in cancer patients, combined with IFNγ/CCR2-blocking protocols to minimize irAEs.
