Myocardial expression of immune checkpoint molecules in patients with advanced heart failure

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Abstract Introduction Immune checkpoints (ICs) are key regulatory molecules of the adaptive immune response. Immune checkpoint inhibition (ICI) is a novel, revolutionary strategy for the treatment of many cancer types. However, ICIs can lead to various immune-related adverse events, including cardiovascular toxicities, such as myocarditis and heart failure (HF). Based on these, ICs may be essential for preserving cardiac homeostasis. Nevertheless, little is known about the expression of ICs in the healthy and failing human heart. Purpose We aimed to characterize the expression of co-inhibitory ICs in patients with advanced HF. Methods Samples of myocardial tissue were obtained during heart transplantation from heart failure patients with ischemic or non-ischemic etiology. In the screening phase, n = 7 samples were used from each group. In the validation study, altogether 80 samples from failing hearts were used. Our healthy controls (n=6) were organ donors whose hearts were not transplanted due to technical issues. The expression level of different co-inhibitory IC proteins (PD-L1, PD-1, CTLA-4, LAG3, VISTA, and B7-H3) in the heart was characterized via Western blot analysis. Results PD-L1 showed a significant increase in both HF groups while VISTA decreased compared with healthy controls. In the ischemic HF group, LAG3 was also significantly decreased, while it was unaltered in non-ischemic HF. PD-1, CTLA-4, and B7-H3 did not show any significant changes in the HF samples. Next, we validated the results of PD-L1, VISTA, and LAG-3 in a larger cohort. Here, myocardial PD-L1 expression showed a significant negative correlation with left ventricular ejection fraction. Conclusion A negative correlation has been found between cardiac function and the upregulation of myocardial PD-L1 in failing hearts. Investigating the role of immune checkpoints in cardiac homeostasis may help to explain the cardiovascular toxicities of immune checkpoint inhibitors.

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