Cancer therapy may raise heart attack and stroke risks by disrupting immune regulation in arteries

Researchers reveal how immune checkpoint inhibitors disrupt immune regulation in atherosclerotic plaques, increasing heart attack and stroke risks, with impacts influenced by diabetes and lipid-lowering therapies

In a recent study published in Nature Cardiovascular Research, a team led by researchers from the New York University Grossman School of Medicine explored the role of immune checkpoint molecules in human atherosclerosis.

They investigated how cardiometabolic conditions such as diabetes and lipid-lowering therapies impact immune interactions in arterial plaques. By mapping immune checkpoint expression, the study aimed to understand potential cardiovascular risks associated with immune checkpoint inhibitor therapies used in cancer treatment.

About the study

In the present study, the researchers employed single-cell ribonucleic acid (RNA) sequencing (scRNA-seq) to analyze immune checkpoint expression in human atherosclerotic plaques. They examined carotid plaques from 22 patients undergoing carotid endarterectomy and coronary artery tissues to compare atherosclerotic and adaptive intimal thickening (healthy controls). They identified over 69,000 immune cells across nine major and 69 subtypes using scRNA-seq, delineating a detailed immune landscape.

Additionally, advanced ligand-receptor interaction mapping was also performed to study immune checkpoint-mediated cell communication, focusing on molecules such as CTLA4, PD-1, LAG3, and others targeted by investigational immune checkpoint inhibitors that have been approved by the Food and Drug Administration (FDA).

Dendritic cells expressing C-C Chemokine Receptor 7 (CCR7+) and fascin actin-bundling protein 1 (FSCN1+) were given specific attention due to their unique transcriptional signatures and their role as a signaling center in atherosclerotic plaques.

The study also assessed the effects of cardiometabolic factors by evaluating immune checkpoint gene expression in plaques from patients with and without diabetes and those who were being treated with lipid-lowering therapies.

Additionally, lipid-modifying interventions in mice were used to understand the role of cholesterol in immune checkpoint dynamics. Ex vivo experiments with human vascular explants and peripheral blood mononuclear cells were also conducted to test the effects of anti-PD-1 and anti-CTLA4 therapies.

Moreover, the study also included data analysis which incorporated spatial mapping techniques and multiplex immunofluorescence to validate the findings. Immune interactions were examined using artificial intelligence-based cell segmentation and digital pathology. Pathway analysis to identify immune regulatory networks and the influence of immune checkpoint expression on plaque inflammation were also conducted to support the experimental findings.

Results

The findings reported that immune checkpoint molecules are extensively expressed in human atherosclerotic plaques and influence immune cell interactions and inflammation. The study identified CCR7+FSCN1+ dendritic cells as a critical regulatory center, mediating up to 15 co-inhibitory and co-stimulatory interactions, especially those involving T cells. These cells exhibited elevated expression of programmed cell death ligand 1 (PD-L1) and CTLA4 ligand, which indicated their role in plaque inflammation.

Furthermore, immune checkpoints such as PD-1, LAG3, and CTLA4 were primarily expressed in T cells, with differential expression across subsets. For example, PD-1 was predominant in effector memory T cells, while CTLA4 was enriched in regulatory T cells. These patterns suggested distinct immune modulation roles within the plaque environment.

Cardiometabolic factors were also found to influence immune checkpoint expression significantly. In plaques from patients with type 2 diabetes, CCR7+FSCN1+ dendritic cells were reduced, and interactions involving PD-1 and PD-L1 and CTLA4 and its ligand CD86 were downregulated.

Furthermore, lipid-lowering therapies in mice also altered immune checkpoint profiles, reducing inflammatory interactions while upregulating protective molecules like galectin-3.

Moreover, the ex vivo experiments revealed that blocking PD-1 or CTLA4 reinvigorated T cells in plaques, increasing their activation and inflammatory capacity. Treated T cells showed heightened expression of markers linked to cytotoxicity and pro-inflammatory responses. These findings demonstrated that immune checkpoint inhibitors may inadvertently amplify atherogenic immune responses.

Conclusions

Overall, the study revealed the complex role of immune checkpoints in atherosclerosis, which is further shaped by cardiometabolic factors and immune-modifying therapies.

The findings also highlighted the role of CCR7+FSCN1+ dendritic cells as key regulators of immune interactions within plaques and showed that immune checkpoint inhibitors exacerbate inflammation.

These results provided critical insights for mitigating cardiovascular risks in cancer patients undergoing immune checkpoint inhibitor treatment and offered a foundation for designing safer therapeutic strategies.