The role of immune checkpoints in cardiovascular disease

Abstract

Immune checkpoint inhibitors (ICI) are monoclonal antibodies which bind to immune checkpoints (IC) and their ligands to prevent inhibition of T-cell activation by tumor cells. Currently, multiple ICI are approved targeting Cytotoxic T-lymphocyte antigen 4 (CTLA-4), Programmed Death Protein 1 (PD-1) and its ligand PD-L1, and Lymphocyte-activation gene 3 (LAG-3). This therapy has provided potent anti-tumor effects and improved prognosis for many cancer patients. However, due to systemic effects, patients can develop immune related adverse events (irAE), including possible life threatening cardiovascular irAE, like atherosclerosis, myocarditis and cardiomyopathy. Inhibition of vascular IC is associated with increased atherosclerotic burden and plaque instability. IC protect against atherosclerosis by inhibiting T-cell activity and cytokine production, promoting regulatory T-cell differentiation and inducing T-cell exhaustion. In addition, PD-L1 on endothelial cells might promote plaque stability by reducing apoptosis and increasing expression of tight junction molecules. In the heart, IC downregulate the immune response to protect against cardiac injury by reducing T-cell activity and migration. Here, inhibition of IC could induce life-threatening T-cell-mediated-myocarditis. One proposed purpose behind lymphocyte infiltration is reaction to cardiac antigens, caused by decreased self-tolerance, and thereby increased autoimmunity because of IC inhibition. In addition, there are several reports of ICI-mediated cardiomyopathy with immunoglobulin G expression on cardiomyocytes, indicating an autoimmune response. IC are mostly known due to their cardiotoxicity. However, t his review compiles current knowledge on mechanisms behind IC function in cardiovascular disease with the aim of providing an overview of possible therapeutic targets in prevention or treatment of cardiovascular irAEs.

Keywords: CTLA-4; LAG-3; PD-1; atherosclerosis; cardiomyopathy; immune checkpoint inhibitors; immune checkpoints; myocarditis.

FIGURE 1

The effect immune checkpoints PD-1, CTLA-4 and LAG-3 in protection against atherosclerosis, dilated cardiomyopathy, and myocarditis. (A). Immune checkpoints have a protective role in atherosclerosis by reducing inflammation and increasing plaque stability. (B). Myocarditis is dampened by IC through reduction of inflammation and T-cell migration, and suppression of autoimmunity. (C). In dilated cardiomyopathy, PD-1 and CTLA-4 are associated with suppressed autoimmunity and reduced cardiac injury. CTLA-4, Cytotoxic T-Lymphocyte-Associated Protein four; LSECtin, liver sinusoidal endothelial cell lectin; LAG-3, Lymphocyte Activation Gene-3; MHC-II, major histocompatibility complex II; PD-1, programmed death-1; PD-L1/2, programmed death-ligand 1/2. Created with BioRender.com.

FIGURE 2

Downstream signaling and effect of immune checkpoint ligands PD-L1/2, CD80/86 and MHC-II in APCs. PD-1/PD-L1/2 interaction results in inhibition of apoptosis by interference with the IFN induced STAT3/CASP7 pathway. Blocking of this pathway by anti-PD-1 or anti-PD-L1/2 leads to less inhibition of the STAT3/CASP7 pathway and therefore increased apoptotic signaling in the presence of IFN signaling. CTLA-4/CD80/86 binding increases self-tolerance by inducing tryptophane catalyzation. Blocking of CTLA-4 leads to reduced tryptophane catalyzation and reduced self-tolerance. MHC-II/LAG-3 binding results in activation of the PI3K/Akt pathway leading to an increase in survival signals. Therefore, blocking LAG-3 results in less PI3K/Akt activation and a reduction in survival signals. CTLA-4, Cytotoxic T-Lymphocyte-Associated Protein four; FGL1, fibrinogen-like protein one; Gal3, Galectin three; IFN, Interferon; LSECtin, liver sinusoidal endothelial cell lectin; LAG-3, Lymphocyte Activation Gene-3; MHC-II, major histocompatibility complex II; PD-1, programmed cell death-1; PD-L1/2, programmed cell death-ligand 1/2. Created with BioRender.com.