This study utilizes CCR2-targeted PET imaging to non-invasively detect dynamic inflammatory changes in atherosclerosis models following PD1 inhibitor treatment. It reveals the key role of IFNγ in inflammation exacerbation induced by the therapy, providing new directions for the mechanistic investigation of immune-related cardiovascular adverse events.
Literature Overview
The article titled 'Visualizing Immune Checkpoint Inhibitors Derived Inflammation in Atherosclerosis', published in Circulation Research, reviews and summarizes immune checkpoint inhibitors (ICIs) used in cancer therapy and their associated immune-related adverse events (irAEs), particularly their impact on the progression of atherosclerosis. The study focuses on how PD1 inhibitors exacerbate plaque inflammation in atherosclerosis by activating T cells and enhancing IFNγ signaling pathways. It further proposes the use of 64Cu-DOTA-ECL1i PET/CT as a non-invasive method to evaluate and monitor ICI-induced inflammatory changes, providing a foundation for future personalized therapies and mechanistic studies.
Background Knowledge
Immune checkpoint inhibitors (ICIs), such as PD1, PD-L1, and CTLA-4 antibodies, have become crucial tools in cancer therapy, but their immune activation effects also bring significant cardiovascular risks, including accelerated atherosclerosis and myocarditis. Atherosclerosis, as the primary pathological basis of cardiovascular disease, progresses in close association with chronic inflammation, where CCR2+ monocytes/macrophages serve as key drivers of the inflammatory response. Although previous studies have reported the roles of these cells in atherosclerosis, no effective non-invasive imaging techniques were available to assess the dynamic changes in plaque inflammation following ICIs treatment. This study fills this gap by applying the 64Cu-DOTA-ECL1i PET imaging technique to track the pro-inflammatory effects of PD1 inhibitors on atherosclerotic plaques in mouse models. Through time- and dose-dependent experiments combined with single-cell RNA sequencing and molecular assays, the study systematically analyzes the underlying mechanisms. This research provides potential tools for future clinical translation, helping to optimize immunotherapy strategies and reduce cardiovascular side effects.
Research Methods and Experiments
The study employed ApoE-deficient (ApoE−/−) and LDL receptor-deficient (LDLr−/−) mice as atherosclerosis models, which were treated with PD1 antibody, control IgG, or saline injections. CCR2+ monocyte/macrophage dynamic changes in plaque regions were evaluated using 64Cu-DOTA-ECL1i PET imaging, combined with histological staining, flow cytometry, and single-cell RNA sequencing to analyze immune cell composition and gene expression changes. Additionally, the impact of PD1 treatment on inflammatory progression was assessed at different time points (4, 8, 16 weeks) and doses (10 mg/kg and 5 mg/kg). In selected experiments, CD8 or IFNγ antibody interventions were introduced to validate the key roles of these signaling pathways.
Key Conclusions and Perspectives
Research Significance and Prospects
This study provides the first non-invasive imaging evidence linking PD1 inhibitor treatment with the inflammatory response in atherosclerosis, establishing the central role of IFNγ in treatment-induced inflammation. Future research should further evaluate the applicability of this imaging technique in humans and explore how CCR2-targeted imaging can optimize immunotherapy regimens in clinical settings to minimize cardiovascular risks. Additionally, combining IFNγ or CD8-targeted therapies may offer safer immunomodulatory strategies for cancer patients.
Conclusion
By establishing a mouse model of atherosclerosis treated with PD1 antibodies and integrating advanced PET imaging, single-cell RNA sequencing, and molecular biology techniques, this study systematically reveals the mechanisms of exacerbated inflammation following immune checkpoint inhibitor therapy. It demonstrates that PD1 antibody treatment significantly increases CCR2+ monocyte/macrophage infiltration into plaques through T cell activation and enhanced IFNγ signaling, thereby worsening atherosclerotic lesions. This process exhibits time- and dose-dependence and persists after treatment cessation, highlighting the need for cautious cardiovascular risk management in clinical ICI therapy. The 64Cu-DOTA-ECL1i PET imaging technique demonstrates high specificity and serves as a non-invasive tool for monitoring inflammatory changes post-ICI treatment, offering potential strategies for personalized therapy in the future. These findings not only provide new insights into the mechanisms of cardiovascular irAEs in cancer patients but also lay the groundwork for developing intervention strategies targeting CCR2 or IFNγ to reduce adverse cardiovascular effects associated with ICIs.
