Resumen de Role of immune checkpoint receptors in myocarditis
Immune tolerance mechanisms are essential to prevent harmful immune responses to own tissues. Immunomodulatory receptors that are key to maintain the immune tolerance, expressed mainly by T cells, are known as immune checkpoint molecules. These molecules are relevant targets for cancer immunotherapy, as the inhibition of their activity has the ability to enhance anti-tumor immune responses. Nevertheless, un-specific derepression of T cells leads to the development of a wide variety of immune-related adverse event, such as myocarditis. Immune-related myocarditis is a severe complication that is associated with a high mortality rate and demands permanent discontinuation of immune checkpoint inhibitors (ICIs) at the cost of an effective cancer treatment. Little is known about the mechanisms and risk factors behind ICI-associated myocarditis, and robust predictive biomarkers of this disease are needed.
In this study, we describe that CD69 lymphoid receptor plays a non-redundant role to IL-2 receptor in the maintenance of immune tolerance in the heart. Cd69-/- Il2rg-/- (common gamma chain) mice spontaneously develop myocarditis and dilated cardiomyopathy, and suffer premature death. The cardiac disease is due to autoreactive lymphocytes, as deficiency of T- and B-cells prevent the disease development in double-knockout mice. In addition, Cd69-/- Il2rg-/- mice frequently show splenomegaly by increased T cell accumulation in spleen, higher anti-cardiac autoantibodies circulating in plasma and higher IL-17A production than Il2rg-/- animals.
We set a new experimental model of ICI-myocarditis in tumor-bearing Cd69-/- mice. Here, we show that CD69 deficiency confers susceptibility to the induction of myocarditis by the inhibition of the Programmed cell death 1 protein (PD-1). In this model, we observed the over-expression of the specific myocarditis biomarker micro-RNA 721 before cardiac toxicity acute phase, postulating it as an early predictor of ICI-myocarditis. Besides, we describe the implication of Th17 cells in disease initiation and CD8 T cells in effector damage to the heart. Importantly, we reveal that once disease has been triggered in the periphery by Th17 cells, therapy discontinuation does not impede neither cardiac immune infiltration nor subsequent cardiac dysfunction. Together, our data provide insights into the mechanisms, predictive biomarkers, and potential therapeutic targets for ICI-myocarditis.
