Immune checkpoint inhibitor-associated myocarditis: manifestations and mechanisms

Abstract

Immune checkpoint inhibitors (ICIs) have transformed the treatment of various cancers, including malignancies once considered untreatable. These agents, however, are associated with inflammation and tissue damage in multiple organs. Myocarditis has emerged as a serious ICI-associated toxicity, because, while seemingly infrequent, it is often fulminant and lethal. The underlying basis of ICI-associated myocarditis is not completely understood. While the importance of T cells is clear, the inciting antigens, why they are recognized, and the mechanisms leading to cardiac cell injury remain poorly characterized. These issues underscore the need for basic and clinical studies to define pathogenesis, identify predictive biomarkers, improve diagnostic strategies, and develop effective treatments. An improved understanding of ICI-associated myocarditis will provide insights into the equilibrium between the immune and cardiovascular systems.

Figure 1. Immune checkpoints in T cell priming and activation.

(A) Mature, but naive, T cells are primed in secondary lymphoid organs. The priming process requires engagement of the TCR by its specific antigenic ligand, which consists of antigen-derived peptides displayed on the surface of antigen-presenting cells (APCs) in the context of MHC molecules; and costimulatory signals provided, in part, by binding of CD80/86 on the surface of APCs to CD28, which is constitutively present on T cells. Full effector functions are acquired in peripheral tissues when the TCR re-encounters its specific antigenic ligand. Priming and later activation steps also result in induction of CTLA-4 and PD-1, respectively, which are coinhibitory receptors that are expressed on the surface of T cells and function as immune checkpoints. (B) CTLA-4 outcompetes CD28 for binding to CD80/86, thereby attenuating CD28-mediated costimulation, reflecting the stronger affinity of CD80/86 for CTLA-4 as compared with CD28 and the upregulation of CTLA-4 during priming. Following binding by its ligands, PD-L1 and PD-L2 (not shown), PD-1 suppresses T cell activation through cell-intrinsic mechanisms that disrupt signaling downstream of TCR (see main text). Genetic alterations or interferon stimulation in cancer cells can induce PD-L1, providing a mechanism for these cells to evade killing by the immune system. IFN-γ–induced expression of PD-L1 on cardiac endothelial cells also provides a means for the heart to protect itself against T cells. Not shown is the role of Tregs (see main text). (C) Approved ICIs are monoclonal antibodies that bind CTLA-4, PD-1, or PD-L1, thereby disrupting interactions between CD80/86 and CTLA-4 and between PD-1 and PD-L1, respectively.

Figure 2. Example of ICI-associated myocarditis.

A 65-year-old woman with metastatic melanoma treated with ipilimumab (3 mg/kg i.v.) and nivolumab (3 mg/kg i.v.) developed atypical chest pain, dyspnea, and fatigue 12 days later, accompanied by (A) ECG showing sinus rhythm with first-degree atrioventricular block, which progressed to complete heart block. (B) Several hours later, ECG showed ventricular tachycardia, which degenerated to ventricular fibrillation and cardiac arrest. The patient could not be resuscitated. (C) At autopsy, cardiac tissue stained with hematoxylin and eosin showed myocyte degeneration accompanied by a mononuclear cell infiltrate, immunostaining of which showed prominence of CD68, a macrophage marker (not shown). (D) Also seen was marked infiltration of T cells, as shown by immunostaining for CD3. This infiltrate included approximately equal proportions of CD4⁺ and CD8⁺ T cells (not shown). In addition, immunostaining for CD20, a B cell marker, and IgG was not detected (not shown). Scale bar: 0.1 mm. aVR, augmented vector right; aVL, augmented vector left; aVF, augmented vector foot. Reproduced with permission from the New England Journal of Medicine (13).