Abstract 107: Effects Of Immune-checkpoint Inhibitors On Atherosclerosis In Halted Progression Model

Immune checkpoint inhibitor (ICI) treatment in cancer has been linked to atherosclerotic-related cardiovascular events. While ICIs have been shown to aggravate atherosclerosis in mouse models of plaque progression, these models do not reflect the clinical scenario of cancer patients with pre-existing atherosclerosis under lipid-lowering treatments. To address this, we tested the effects of PD1 or CTLA4 inhibitors (aPD1 or aCTLA4), and their combination (aPD1 + aCTLA4), in a model of halted atherosclerosis progression, mimicking standard of care lipid-lowering treatments. Ldlr -/- mice (n=126) mice were fed a western diet (WD) for 17 wk (baseline), followed by a switch to standard chow diet for 4 wk (halted progression), and mice were randomized to treatment arms. Histological and single cell RNA sequencing (scRNA-seq) revealed that inhibiting PD-1 or CTLA-4 individually aggravated atherosclerosis, despite comparable cholesterol reduction to isotype control groups. Surprisingly, the combination of aPD1 + aCTLA4 did not show the same proatherogenic effect observed individually. Distinct effects on plaque composition were noted, with aPD-1 or aCTLA4 leading to increased plaque collagen content, and their combination showing plaque stabilization with higher cap thickness and similar collagen content to controls. Immunostaining revealed no differences in plaque macrophage content among groups, but aPD-1-treated mice exhibited increased CD8 T cells. scRNAseq showed that aPD1 increased specific inflammatory myeloid clusters, including Spp1+ macrophages and Ccr2+ MoDCs, and reduced anti-inflammatory IL16+ DPTs but increased cytotoxic Gzmk+ CD8+ EMRA T cells. CTLA4 inhibition increased foamy Trem2hi macrophages and Ccr2+ MoDCs. Yet, combined aPD1 + aCTLA4 did not significantly alter cell proportions compared to halted progression. In conclusion, our study demonstrates that inhibiting either PD1 or CTLA4 individually aggravates atherosclerosis, under cholesterol lowering conditions. These findings highlight the nuanced effects of immune checkpoint inhibitors on atherosclerosis, emphasizing the potential importance of considering combination therapies and lipid lowering for better outcomes in cancer survivors.