Molecular fingerprints of cardiovascular toxicities of immune checkpoint inhibitors

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy by unleashing the power of the immune system against malignant cells. However, their use is associated with a spectrum of adverse effects, including cardiovascular complications, which can pose significant clinical challenges. Several mechanisms contribute to cardiovascular toxicity associated with ICIs. First, the dysregulation of immune checkpoints, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein-1 (PD-1) and its ligand (PD-L1), and molecular mimicry with cardiac autoantigens, leads to immune-related adverse events, including myocarditis and vasculitis. These events result from the aberrant activation of T cells against self-antigens within the myocardium or vascular endothelium. Second, the disruption of immune homeostasis by ICIs can lead to autoimmune-mediated inflammation of cardiac tissues, manifesting as cardiac dysfunction and heart failure, arrhythmias, or pericarditis. Furthermore, the upregulation of inflammatory cytokines, particularly tumor necrosis factor-alpha, interferon-γ, interleukin-1β, interleukin-6, and interleukin-17 contributes to cardiac and endothelial dysfunction, plaque destabilization, and thrombosis, exacerbating cardiovascular risk on the long term. Understanding the intricate mechanisms of cardiovascular side effects induced by ICIs is crucial for optimizing patient care and to ensure the safe and effective integration of immunotherapy into a broader range of cancer treatment protocols. The clinical implications of these mechanisms underscore the importance of vigilant monitoring and early detection of cardiovascular toxicity in patients receiving ICIs. Future use of these key pathological mediators as biomarkers may aid in prompt diagnosis of cardiotoxicity and will allow timely interventions.

Keywords: Autoimmune; Cardiotoxicity; Immune-related adverse event; Immunotherapy.

Fig. 1

Immune checkpoint inhibition in cancer therapy and its cardiovascular adverse effects. (Left) Inhibition of immune checkpoints via monoclonal antibodies is an effective pharmacological strategy for anti-cancer treatment. (Right) Immune checkpoint inhibition is associated with immune-related adverse events, including cardiovascular side effects. These include myocarditis, cardiac dysfunction or heart failure, progression of atherosclerosis and atherosclerotic cardiovascular disease (ASCVD), vasculitis, pericardial disease, and venous thromboembolism (VTE). LAG-3: lymphocyte-activation gene-3, PD-1: programmed cell death protein-1, PD-L1: programmed death ligand-1, CTLA-4: cytotoxic T-lymphocyte-associated protein 4. Created with Biorender.com

Fig. 2

Immune checkpoint inhibitor (ICI)-induced myocarditis. ICI myocarditis is a rare, but fatal cardiac adverse event. Potential mechanisms include systemic factors, such as changes in circulatory immune cells, clonal T-cell expansion due to shared antigens between the tumor cells, cardiomyocytes, and skeletal muscle cells, and the central role of the thymus. Local alterations in the myocardium include immune cell infiltration, crosstalk between T cells and macrophages, and cardiac-specific antigen recognition by T cells, while changes in estrogen hormone levels may alter local cardioprotective signaling. CCL5: chemokine (C–C motif) ligand 5, CCL4: chemokine (C–C motif) ligand 4, CCL4L2: chemokine (C–C motif) ligand 4 like 2, MYH6: myosin heavy chain 6, AChR: acetylcholine receptor, CCR2: C–C chemokine receptor type 2, CXCR3: C-X-C motif chemokine receptor 3, CXCL9/10: C-X-C motif chemokine ligand 9/10, PD-1: programmed cell death protein-1, CTLA-4: cytotoxic T-lymphocyte-associated protein 4, MANF: mesencephalic astrocyte-derived neurotrophic factor. Created with Biorender.com

Fig. 3

Immune checkpoint inhibitors and cardiac dysfunction or heart failure. Cardiac dysfunction can occur as an early or late adverse event after ICI treatment, with various presentations, including asymptomatic left ventricular (LV) dysfunction, Takotsubo syndrome, acute heart failure (HF), or chronic HF including HF with reduced ejection fraction (HFrEF) or with preserved ejection fraction (HFpEF). Potential mechanisms include pro-inflammatory cytokine release, autoantibodies, disruption of myocardial homeostasis and the role of the thymus. TNFα: tumor necrosis factor-alpha, IL-17: interleukin-17, IL-1β: interleukin-1β, IL-6: interleukin-6, cTnI: cardiac troponin I, PD-L1: PD-L1: programmed death ligand-1, IL-3: interleukin-3, IL-23: interleukin-23. Created with Biorender.com

Fig. 4

Immune checkpoint inhibitor-induced atherosclerotic cardiovascular disease (ASCVD). Immune checkpoint inhibition may contribute to ASCVD by promoting plaque progression or by increasing dyslipidemia. Overall, an increase in major adverse cardiovascular events is observed after ICI therapy. Potential mechanisms include T-cell expansion and activation in the atherosclerotic plaques, crosstalk between T cells and macrophages leading to macrophage activation, and the release of pro-inflammatory cytokines. Inflammation in the plaque results in foam cell formation, intimal thickening, increased necrotic core and decreased collagen content. IFNγ: interferon-γ, TNFα: tumor necrosis factor alpha, IL-1β: interleukin-1β, IL-6: interleukin-6. Created with Biorender.com

Fig. 5

Immune checkpoint inhibitor-induced arrhythmias and conduction disorders. ICI-induced electrophysiological disorders are often associated with ICI myocarditis and include atrioventricular blocks, as well as supraventricular and ventricular tachyarrhythmias. Potential, hypothetical mechanisms include re-entry through myocardial scar formation, alteration of immune cells (e.g., macrophages) important in physiological electrical conduction in the myocardium, and autoantibody formation, although mechanistic studies are needed to confirm these hypotheses. MACE: major adverse cardiovascular events. Created with Biorender.com