Atherosclerosis With Immune Checkpoint Inhibitor Therapy: Evidence, Diagnosis, and Management: JACC: CardioOncology State-of-the-Art Review

Abstract

As the clinical applications of immune checkpoint inhibitors (ICIs) expand, our knowledge of the potential adverse effects of these drugs continues to broaden. Emerging evidence supports the association between ICI therapy with accelerated atherosclerosis and atherosclerotic cardiovascular (CV) events. We discuss the biological plausibility and the clinical evidence supporting an effect of inhibition of these immune checkpoints on atherosclerotic CV disease. Further, we provide a perspective on potential diagnostic and pharmacological strategies to reduce atherosclerotic risk in ICI-treated patients. Our understanding of the pathophysiology of ICI-related atherosclerosis is in its early stages. Further research is needed to identify the mechanisms linking ICI therapy to atherosclerosis, leverage the insight that ICI therapy provides into CV biology, and develop robust approaches to manage the expanding cohort of patients who may be at risk for atherosclerotic CV disease.

Keywords: ASCVD, atherosclerotic cardiovascular disease; CTLA-4, cytotoxic T-lymphocyte associated protein 4; ICI, immune checkpoint inhibitor; IFN, interferon; IL, interleukin; PD-1, programmed cell death protein 1; PD-L1, programmed cell death ligand 1; TNF, tumor necrosis; atherosclerosis; cardio-oncology; cardiovascular disease; immune checkpoint inhibitor; inflammation; irAE, immune-related adverse event.

Graphical abstract

Central Illustration

Effects of Immune Checkpoint Alterations Immune checkpoint inhibitors (ICIs) cause an enhanced immune response and persistent inflammation. Several pathways are being implicated in post-ICI aggravated atherosclerosis, with the strongest evidence for the co-inhibitory blockade via the cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) and the co-stimulatory agonism of CD40/CD40L and glucocorticoid-induced tumor necrosis factor family-related protein (GITR) pathways. Costimulatory molecules were B7.1= CD80 and B7.2 = CD86. APC = antigen-presenting cell; GITRL = glucocorticoid-induced tumor necrosis factor family-related protein ligand; ICAM= intracellular adhesion molecule; ICOS = inducible costimulatory; IFN = interferon; IL = interleukin; LAG-3 = lymphocyte activation gene 3; MHC = major histocompatibility complex; MI = myocardial infarction; MMP = matrix metalloproteinase; NK = natural killer; SIRP = signal-regulatory protein; TCR = T cell receptor; TGF = transforming growth factor; Th1 = T helper 1; TIM-3 = T cell immunoglobulin and mucin containing domain-3; TNF = tumor necrosis factor; Treg = regulatory T; VCAM = vascular cell adhesion molecule.

Figure 1

Management Considerations in ICI-Associated Atherosclerosis Management strategies for immune checkpoint inhibitors (ICI)–treated patients can include monitoring of atherosclerotic burden pre- and post-ICI therapy with serum and imaging biomarkers, and implementation of tailored interventions. Created with BioRender. CT = computed tomography; CCTA = coronary computer tomography angiography; FDA = Food and Drug Administration; hsCRP = high sensitivity C-reactive protein; IL = interleukin; MCP = monocyte chemoattractant protein; MRI = magnetic resonance imaging; Ox LDL = oxidized low density lipoprotein; PD-1 = programmed cell death protein 1; PD-L1 = programmed cell death ligand 1; sCD = serum cluster differentiation; PET = positron emission tomography; TNF = tumor necrosis factor; VCAM = vascular cell adhesion molecule.