PET, Proteomics, and Immunophenotyping of Arterial Inflammation and Checkpoint Inhibition

Importance Immune checkpoint inhibitors (ICIs) have transformed cancer outcomes but may be associated with an increased risk of myocardial infarction and ischemic stroke. Whether this risk is mediated by inflammatory plaque activation and whether coadministered vascular endothelial growth factor inhibitors (VEGFIs) modify the effect remain unresolved. Objective To prospectively characterize the arterial and systemic inflammatory outcomes associated with ICIs, VEGFIs, and combined ICIs plus VEGFIs in patients with cancer. Design, Setting, and Participants This prospective longitudinal cohort study was conducted between August 2022 and June 2024 at the West of Scotland regional cancer hospital network. Adults with cancer who were planned to receive ICI monotherapy, VEGFI monotherapy, or combined ICI plus VEGFI therapy underwent imaging and venous blood sampling at baseline (before treatment) and at 24 weeks. Data were analyzed from June 2024 to October 2025. Exposure Undergoing ( 18 F)fluorodeoxyglucose positron emission tomography computed tomography ([ 18 F]FDG-PET/CT) imaging. Main Outcomes and Measures Arterial inflammation was quantified by ( 18 F)FDG-PET/CT using imaging protocols optimized for vascular assessment. The primary outcome was the between-group difference in change in maximal tissue to background ratio (TBRmax) over time, evaluated by analysis of covariance adjusted for baseline. Systemic inflammatory biomarkers were measured by enzyme-linked immunosorbent assay and a proteomic panel. Circulating immune cell phenotypes were profiled using spectral flow cytometry. Results Of 55 evaluable patients (mean [SD] age, 66 [10] years; 39 male [71%] and 16 female [29%]), 20 received ICIs, 15 received VEGFIs, and 20 received ICIs plus VEGFIs. At 24 weeks, TBRmax did not exceed baseline in any group (ICIs: mean [SD], 1.71 [0.14] vs 1.67 [0.14]; VEGFIs: mean [SD], 1.72 [0.22] vs 1.72 [0.17]; ICIs + VEGFIs: mean [SD], 1.74 [0.18] vs 1.64 [0.15]; among groups: P = .13). Findings were consistent across artery type, calcification status, prior atherosclerotic disease, and steroid exposure. ICI therapy was associated with selectively altered T-cell subsets, an outcome attenuated by concurrent VEGFI therapy, while VEGFI therapy alone had no significant association with circulating immune cells. Across all 3 regimens, systemic inflammatory biomarkers showed only modest changes. Intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 increased in patients exposed to ICIs. Conclusions and Relevance In this prospective cohort study, ICIs and VEGFIs, alone and in combination, were not associated with ( 18 F)FDG-PET/CT–detectable arterial inflammation, and systemic inflammatory outcomes were limited. These findings argue against macrophage-driven plaque activation as a primary mechanism of ICI-associated atherothrombosis and support prioritization of endothelial and thrombotic pathways in future mechanistic and preventive studies.