Visualizing Immune Checkpoint Inhibitors Derived Inflammation in Atherosclerosis

Area of Science:

• Cardiovascular Research
• Immunology
• Radiochemistry

Background:

• Immune checkpoint inhibitors (ICIs) can cause immune-related adverse events, including accelerated atherosclerosis.
• Proinflammatory CCR2+ macrophages play a key role in atherosclerosis, but noninvasive methods to track them during ICI treatment are lacking.
• Understanding these mechanisms is crucial for managing ICI-related cardiovascular complications.

Purpose of the Study:

• To develop and validate a noninvasive positron emission tomography (PET) imaging approach to assess CCR2+ macrophage accumulation in atherosclerosis.
• To investigate the underlying mechanisms of immune-related adverse events, specifically accelerated atherosclerosis, following ICI treatment.
• To explore the potential of CCR2-targeted PET for monitoring plaque inflammation in vivo.

Main Methods:

• Atherosclerosis-prone mice (Apoe-/- and Ldlr-/-) were treated with anti-PD1 antibody (ICI) or control IgG/saline.
• ⁶⁴Cu-DOTA-ECL1i, a novel CCR2-targeted radiotracer, was used for PET imaging.
• Immunohistochemistry, flow cytometry, and single-cell RNA sequencing were employed for molecular characterization of atherosclerotic arteries.

Main Results:

• PET imaging revealed significantly higher ⁶⁴Cu-DOTA-ECL1i uptake in ICI-treated mice, indicating increased CCR2+ macrophage accumulation.
• Immunostaining and flow cytometry confirmed elevated CCR2+ cell populations in the atherosclerotic plaques of treated mice.
• Single-cell RNA sequencing identified increased CCR2 expression in myeloid cells, and interferon-gamma (IFNγ) was found to be essential for the aggravated inflammation and plaque progression.

Conclusions:

• ⁶⁴Cu-DOTA-ECL1i PET can noninvasively detect accelerated atherosclerotic plaque inflammation induced by anti-PD1 therapy.
• The observed inflammation is dose- and time-dependent and primarily mediated by IFNγ signaling.
• CCR2-targeted PET shows promise as a tool for visualizing plaque inflammation and exploring mechanisms of ICI-related adverse events.