Immune checkpoints in cardiac physiology and pathology: therapeutic targets for heart failure

Immune checkpoint molecules are physiological regulators of the adaptive immune response. Immune checkpoint inhibitors (ICIs), such as monoclonal antibodies targeting programmed cell death protein 1 or cytotoxic T lymphocyte-associated protein 4, have revolutionized cancer treatment and their clinical use is increasing. However, ICIs can cause various immune-related adverse events, including acute and chronic cardiotoxicity. Of these cardiovascular complications, ICI-induced acute fulminant myocarditis is the most studied, although emerging clinical and preclinical data are uncovering the importance of other ICI-related chronic cardiovascular complications, such as accelerated atherosclerosis and non-myocarditis-related heart failure. These complications could be more difficult to diagnose, given that they might only be present alongside other comorbidities. The occurrence of these complications suggests a potential role of immune checkpoint molecules in maintaining cardiovascular homeostasis, and disruption of physiological immune checkpoint signalling might thus lead to cardiac pathologies, including heart failure. Although inflammation is a long-known contributor to the development of heart failure, the therapeutic targeting of pro-inflammatory pathways has not been successful thus far. The increasingly recognized role of immune checkpoint molecules in the failing heart highlights their potential use as immunotherapeutic targets for heart failure. In this Review, we summarize the available data on ICI-induced cardiac dysfunction and heart failure, and discuss how immune checkpoint signalling is altered in the failing heart. Furthermore, we describe how pharmacological targeting of immune checkpoints could be used to treat heart failure. In this Review, Varga and colleagues provide an overview of the evidence on immune checkpoint inhibitor-induced heart failure and cardiac dysfunction that is unrelated to myocarditis, and discuss how pharmacological targeting of immune checkpoints might be a potential strategy to treat heart failure. Immune checkpoint inhibitors have revolutionized cancer treatment, but their use is associated with immune-related adverse events, including cardiovascular adverse effects.Among the cardiovascular adverse events associated with immune checkpoint inhibitors, myocarditis is the most studied, but heart failure is increasingly being recognized.Immune checkpoint signalling is involved in several physiological and pathological processes in the heart.Modulation of immune checkpoint signalling can result in cardiac dysfunction or provide a target for therapeutic interventions in the failing heart, depending on the targeted checkpoint.