运动减轻老年荷黑色素瘤小鼠主动脉中抗 PD-1 诱导的外膜巨噬细胞炎症

Immune checkpoint inhibitors (ICI) improve cancer outcomes but can induce vascular toxicity, potentially threatening long-term survivorship. In our pilot data using young male mice with tumors, anti-PD-1 increased vimentin, an endothelial-to-mesenchymal transition (EndMT) marker linked to early atherosclerosis, in laminar-flow regions of the aorta, and exercise attenuated this response. Given the rapid growth of our melanoma model and the greater vulnerability of aged mice to ICI-associated vascular injury, we used aged mice to capture early vascular responses and determine whether exercise modifies anti-PD-1-induced vascular inflammation. One-year-old female C57BL/6J mice were injected subcutaneously with BP melanoma cells. Once tumors became measurable, mice were assigned to three treatment groups: control IgG (N=12), anti-PD-1 (aPD-1, 150 μg × 5 doses = 750 μg total; N=9), or anti-PD-1 plus moderate treadmill exercise (aPD1+Ex, N=8) for two weeks. Tumor growth was monitored every other day. Thoracic aortas were collected, embedded as FFPE tissue microarrays, and scanned by multiplex immunofluorescence, and analyzed in Visiopharm for tissue segmentation (intima, media, adventitia), cell identification, and immune/vascular phenotyping. Exercise plus aPD-1 suppressed tumor growth significantly better than aPD-1 alone (~60% reduction vs. IgG; p = 0.04). Across cross-sectioned aortic rings containing ~706 total cells on average (19,069 cells across 29 vessels), whole-vessel counts of CD4 + , CD8 + , and B220 + cells were uniformly low across groups. B220 + cells showed a polarized pattern in the aPD-1 group, with elevated counts in only a subset of mice. In contrast, aPD-1 increased adventitial F4/80⁺ macrophages more than 2.5-fold relative to IgG (N.S.), consistent with early adventitial-driven vascular inflammation. Importantly, exercise significantly reduced adventitial infiltration accumulation (p=0.03). Additional spatial analyses of vascular inflammation and immune-vascular interactions are ongoing. In aged tumor-bearing mice, anti-PD-1 induces early aortic vascular toxicity characterized by adventitial macrophage inflammation, paralleling early inflammatory patterns reported in early human large-vessel vasculitis associated with ICI therapy. Exercise markedly attenuates this adventitial macrophage-driven vascular response without compromising antitumor efficacy, suggesting its potential as a non-pharmacologic strategy to mitigate early ICI-associated vascular injury.