Immune checkpoints in cardiovascular disease

Abstract

The balance between fast antigen clearance while avoiding autoinflammation is regulated via numerous stimulatory and inhibitory signals, called immune checkpoints. Dysregulation of the immune checkpoints can cause serious immune related adverse effects (irAE), including possible life threatening immune related cardiovascular adverse effects (irCVAE), like atherosclerosis, myocarditis and myocardiopathy. However rare, these irCVAE are also seen in treatment with immune checkpoint inhibitors (ICIs) in cancer treatment. Currently multiple ICIs are approved targeting CTLA-4, PD-1, PD-L1 and LAG3. Inhibition of immune checkpoints is associated with increased atherosclerotic burden and plaque instability. The immune checkpoints protect against atherosclerosis by inhibiting T lymphocyte activity and cytokine production, promoting regulatory T cell (Treg ) differentiation and inducing T cell exhaustion. In addition, PD-L1 and MHC-II on endothelial cells might promote plaque stability by reducing apoptosis and increasing expression of tight junction molecules. In the heart immune checkpoints downregulate the immune response to protect against cardiac injury by reducing T lymphocyte activity and migration. The inhibition of immune checkpoints results could induce life-threatening lymphocyte myocarditis. One of the proposed reasons of lymphocyte infiltration is reaction to cardiac striated muscle antigens, caused by decreased self-tolerance, and thereby increased autoimmunity as a result of immune checkpoint inhibition. In addition, there are some reports of ICI induced cardiomyopathy with IgG disposition on myocytes, indicating an autoimmunity response. This review will address the mechanisms behind the protective function of immune checkpoints against cardiovascular disease by describing the direct inhibitory effect on T cell immunity, as well as the reverse signaling of immune checkpoint ligands in endothelial cells and APCs.