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Review
. 2022 Sep 16;14(18):4494.
doi: 10.3390/cancers14184494.

Pathophysiology of Immune Checkpoint Inhibitor-Induced Myocarditis

Rosa Jiménez-Alejandre  1 , Ignacio Ruiz-Fernández  1 , Pilar Martín  1   2
Affiliations
Review

Pathophysiology of Immune Checkpoint Inhibitor-Induced Myocarditis

Rosa Jiménez-Alejandre et al. Cancers (Basel). .

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.

Keywords: ICI-myocarditis; T cells; anti-CTLA-4; anti-PD-1; cancer therapy; cardiotoxicity; immunotherapy; irAEs; myocarditis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Immune checkpoint molecules. T cells become active upon binding of the TCR to the MHC-antigen complex followed by CD28 co-stimulation both provided by APCs. Both LAG-3 and CTLA-4 limit these interactions via direct competition, hence rendering T cell activation and subsequent proliferation and cytokine production. On the other hand, PD-1 and PD-L1/L2 binding on the target cells also contribute to limit the immune response by induction of apoptosis and exhaustion on T cells. These are also targeted by monoclonal antibodies to enhance immune responses in a cancer setting.
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