Immune checkpoint inhibitor–associated myocarditis: manifestations and mechanisms
Javid Moslehi, Andrew H. Lichtman, Arlene H. Sharpe, Lorenzo Galluzzi, Richard N. Kitsis
Javid Moslehi, Andrew H. Lichtman, Arlene H. Sharpe, Lorenzo Galluzzi, Richard N. Kitsis
View: Text | PDF
Review

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.

Authors

Javid Moslehi, Andrew H. Lichtman, Arlene H. Sharpe, Lorenzo Galluzzi, Richard N. Kitsis

×

Figure 1

Immune checkpoints in T cell priming and activation.

Options: View larger image (or click on image) Download as PowerPoint
Immune checkpoints in T cell priming and activation. (A) Mature, but nai...
(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.