Melanoma, Immunotherapy, and Atherosclerosis: A new model for mechanistic discovery

Hyperlipidemia is a well-established driver of atherosclerosis in cardiovascular patients, primarily through the increased production of myeloid cells, including monocytes, macrophages, neutrophils, and dendritic cells. These myeloid cells are critical components of innate and adaptive immunity and play a central role in the initiation and progression of atherosclerotic plaques. Recent evidence has revealed a similar phenomenon in melanoma patients, where enhanced myelopoiesis leads to elevated levels of pro-inflammatory cytokines, including IL-1β, TNF-α, and IL-6. These cytokines are key mediators of residual inflammatory risk and contribute significantly to the development of atherosclerosis.

Immune checkpoint inhibitors (ICIs), such as anti-CTLA-4 therapies like ipilimumab, amplify myelopoiesis and the production of inflammatory cytokines, including TNF-α, IL-6, and IFN-γ. While these effects enhance immune responses against melanoma, they also exacerbate systemic inflammation, which can contribute to vascular dysfunction. Notably, melanoma patients treated with ICIs have a twofold increased risk of developing atherosclerosis compared to those without melanoma.

Despite this established connection, the mechanisms by which melanoma and its therapies contribute to atherosclerotic plaque instability remain poorly understood. The potential for heightened production of immune cells and inflammatory cytokine production to destabilize plaques, thereby increasing the risk of cardiovascular events, is an emerging and critical area of investigation.

Aim 1: To develop novel mouse models to investigate the effects of melanoma and its treatment on unstable atherosclerotic plaques at the single-cell level.

Aim 2: To evaluate the effects of ICIs on the development and progression of melanoma-induced atherosclerosis in established mouse models.

Melanoma patients, especially those receiving ICIs, face a significantly increased risk of atherosclerosis due to systemic inflammation and vascular dysfunction. However, the mechanisms by which melanoma influences plaque progression are poorly understood, and no suitable mouse models exist. This study will develop novel lineage-traced tandem stenosis (TS) mouse models to label endothelial and smooth muscle cells. Melanoma will be induced via B16-BL6 injections, enabling single-cell level analysis of tumor-vascular interactions driving plaque instability.

This project will establish novel preclinical models that mimic the melanoma-atherosclerosis axis observed in patients. Insights from single-cell analysis will identify key molecular drivers of plaque instability induced by melanoma and ICI therapy. These targets can inform biomarker discovery for early vascular risk prediction in melanoma patients. Findings will guide the development of therapeutic strategies to mitigate cardiovascular risk without compromising cancer treatment efficacy. Ultimately, this work lays the foundation for clinical studies integrating vascular monitoring into melanoma care.

Murine models of melanoma and atherosclerosis, cardiovascular genetics, confocal microscopy, molecular biology.