Accelerated atherosclerosis associated with immune checkpoint inhibitors: a systematic review and meta-analysis of pre-clinical studies

Volume 405, June 2025, 119219

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Inhibition of co-inhibitory immune checkpoint proteins results in a 53% increase in atherosclerotic plaque size in mice

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Plaque composition was predominantly characterized by a greater abundance of CD4+ T cells, CD8+ T cells and macrophages.

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Reduction in plaque size and inflammation was observed upon stimulation of the co-inhibitory immune checkpoint proteins.

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ICI-induced atherosclerosis in mice may reflect the cause of the increased cardiovascular event risk in patients with ICI.

AbstractBackground

Patients with cancer treated with immune checkpoint inhibitors are at increased risk of myocardial infarction and ischemic stroke. The mechanism is incompletely understood but may involve accelerated atherosclerosis due to enhanced inflammation. Pre-clinical studies may provide insight in these mechanisms.

Aim

To assess the effects of modulating co-inhibitory immune checkpoint proteins on atherosclerosis progression in animal models.

Methods

A systematic review was performed in MEDLINE, Embase, Web of Science, and Scopus up to March 2025. Animal studies were included if the effect of modulation of programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte associated protein 4 (CTLA-4), and/or lymphocyte-activation gene 3 (LAG-3) on atherosclerotic plaque size was evaluated. Secondary outcomes were plaque composition and systemic inflammation. The ratios of means (RoM) across the studies were pooled in a random effects meta-analysis. Risk of bias was assessed using the SYRCLE tool, focusing on randomization, blinding, and completeness of outcome reporting.

Results

Fourteen eligible studies were included. All studies used an atherosclerotic mouse model (ApoE−/−, Ldlr−/−, ApoE3∗Leiden, or AAV8-PCSK9) and either evaluated pharmacological or genetic modulation of co-inhibitory immune checkpoint proteins. Upon inhibition, atherosclerotic plaque size in the aorta was 53 % higher in exposed mice compared to control mice (RoM, 1.53; 95 % CI, 1.29–1.83; I2 = 89 %). Plaque composition was predominantly characterized by a greater abundance of CD4+ T cells, CD8+ T cells, and macrophages. Studies stimulating co-inhibitory immune checkpoint proteins corroborated these findings and demonstrated that atherosclerotic plaque size was reduced by 28 % in treated mice compared to controls (RoM, 0.72; 95 % CI, 0.65–0.80; I2 = 85 %). This reduction was paralleled by a decrease in the number of macrophages and T cells in plaques.

Conclusion

Immune checkpoint inhibition leads to increased plaque inflammation and a significant increase in murine atherosclerotic plaque size. These changes may reflect the cause of the increased risk of myocardial infarction and ischemic stroke in patients treated with immune checkpoint inhibitors.

Graphical abstractInhibition of co-inhibitory immune checkpoint proteins leads to increased plaque inflammation, plaque size and systemic inflammation in murine models. Created in https://BioRender.com.