Pathophysiology of Immune Checkpoint Inhibitor-Induced Myocarditis

SIMPLE SUMMARY: Myocarditis is an infrequent but highly hazardous complication of the cancer therapy of immune checkpoint inhibitors (ICIs). The study of the pathophysiology of this disease is an active field of research and a clearer comprehension of the mechanisms is crucial to provide an accurate diagnosis, appropriate therapy, and to prevent cardiac adverse toxicities occurring during ICI treatment that compromise the continuation of the cancer treatment. This review provides an update of the currently approved ICIs and their relationship with myocarditis induction through boosting the immune system. It also discusses preclinical models of ICI-associated myocarditis and their contribution to the state of the art and presents recent advances in the pathogenesis of the disease. ABSTRACT: Immune checkpoint inhibitors (ICIs) have recently emerged as strong therapies for a broad spectrum of cancers being the first-line treatment for many of them, even improving the prognosis of malignancies that were considered untreatable. This therapy is based on the administration of monoclonal antibodies targeting inhibitory T-cell receptors, which boost the immune system and prevent immune evasion. However, non-specific T-cell de-repression can result in a wide variety of immune-related adverse events (irAEs), including gastrointestinal, endocrine, and dermatologic, with a smaller proportion of these having the potential for fatal outcomes such as neurotoxicity, pulmonary toxicity, and cardiotoxicity. In recent years, alarm has been raised about cardiotoxicity as it has the highest mortality rate when myocarditis develops. However, due to the difficulty in diagnosing this cardiac condition and the lack of clinical guidelines for the management of cardiovascular disease in patients on therapy with ICIs, early detection of myocarditis has become a challenge in these patients. In this review we outline the mechanisms of tolerance by which this fatal cardiomyopathy may develop in selected cancer patients treated with ICIs, summarize preclinical models of the disease that will allow the development of more accurate strategies for its detection and treatment, and discuss the challenges in the future to decrease the risks of its development with better decision making in susceptible patients.