Cardiac Complications in Immune Checkpoint Inhibition Therapy

Abstract

Immune checkpoint inhibitors (ICIs) have changed the treatment landscape of advanced cancers. Unfortunately, these agents can induce a wide spectrum of immune-related adverse events (irAEs) through activation of immune responses in non-target organs, including the heart. As the clinical use of ICI therapy increases rapidly, management of irAEs is becoming extremely important. The most commonly presented cardiac irAE is myocarditis. Histopathologically, T-cell (with a predominance of CD8⁺ cells) and macrophage infiltration in the myocardium is typically observed in ICI-associated myocarditis. Other presentations of cardiac irAEs include congestive heart failure, Takotsubo cardiomyopathy, pericardial disease, arrhythmias, and conduction disease. Although cardiac irAEs are relatively rare, they can be life-threatening. Hence, cardiologists and oncologists should be vigilant for these presentations.

Keywords: autoimmunity; cardiotoxicity; cytotoxic T-lymphocyte antigen 4; immune checkpoint; immune checkpoint inhibitors; immune-related adverse events; myocarditis; programmed cell death protein 1.

Figure 1

Distinct roles of CTLA-4 and PD-1/PD-L1 in the regulation of antitumor immune responses. (A) Interactions between CTLA-4/B7 and PD-1/PD-L1 inhibit T cell-mediated tumor cell killing. (B) Blockade of CTLA-4, PD-1, and PD-L1 results in T cell activation and proliferation, which reactivates T cell-mediated tumor cell killing.

Figure 2

The clinical spectrum of irAEs associated with immune checkpoint inhibitors. irAEs, immune-related adverse events.

Figure 3

The role of immune checkpoints in establishing peripheral tolerance to the heart. During the establishment of central tolerance in the thymus, most autoreactive T cells are deleted; however, some autoreactive T cells are released into the periphery. In health, peripheral tolerance mechanisms keep these cells in check. CTLA-4 competes with CD28 to downregulate T-cell activation, resulting in immunotolerance and prevention of pathologic immune responses to cardiac-antigens. PD-1-PD-1 ligand interactions also maintain the cardiac-reactive T cells in an anergic state. Antibodies against CTLA-4, PD-1, or PD-L1 may activate cardiac antigen-reactive T cells that escape central tolerance. These T cells can clonally expand and attack the heart.