Objective:

To investigate the effect of the immune checkpoint inhibitor nivolumab on vascular smooth muscle cells (SMCs) in the context of increased atherosclerotic cardiovascular disease (ASCVD) risk.

Approach:

• Cell Culture and Treatment: Cultured human SMCs were treated with nivolumab and assessed for activation of heat shock factor 1 (HSF1), HMG-CoA reductase (HMGCR), and endoplasmic reticulum (ER) stress signaling, with specific outcomes measured including cholesterol accumulation.
• Mechanistic Analysis: The study evaluated the role of HSF1 activation in cholesterol biosynthesis and SMC phenotypic modulation, as well as the effects of PD-1 neutralization and pravastatin treatment on these processes.

Key Findings:

• Nivolumab treatment induced activation of HSF1 and increased HMGCR activity, leading to cholesterol accumulation in SMCs, which may contribute to ASCVD risk.
• Activation of PERK signaling was observed, contributing to atherosclerosis-associated phenotypic changes in SMCs.
• Neutralization and knockdown of PD-1, as well as treatment with pravastatin, reversed nivolumab-induced effects on cholesterol synthesis and SMC phenotype.

Interpretation:

Nivolumab induces stress signaling pathways in SMCs that contribute to increased ASCVD risk, independent of plasma cholesterol levels.

Limitations:

• The study was conducted in vitro, and further in vivo studies are needed to confirm findings and assess the impact of ICI treatment on ASCVD risk across diverse patient populations.
• Potential confounding factors related to patient demographics and comorbidities were not addressed.

Conclusion:

The findings suggest a rationale for statin therapy to mitigate ICI-induced ASCVD risk, even in patients with normal cholesterol levels.