Anti-PD-1 treatment induced cardiac dysfunction and left ventricular dilation in C57BL/6J mice, which was prevented by pharmacological inhibition of IL-17A.
Does anti-PD-1 treatment induce cardiac dysfunction in mice, and does IL-17A inhibition prevent it?
Pharmacological inhibition of IL-17A prevents anti-PD-1-induced cardiac dysfunction in a mouse model, highlighting a potential therapeutic target for immune checkpoint inhibitor-induced cardiotoxicity.
BACKGROUND AND PURPOSE: Immune checkpoint inhibitors (ICI), such as anti-PD-1 monoclonal antibodies, have revolutionized cancer therapy by enhancing the cytotoxic effects of T-cells against tumours. However, enhanced T-cell activity also may cause myocarditis and cardiotoxicity. Our understanding of the mechanisms of ICI-induced cardiotoxicity is limited. Here, we aimed to investigate the effect of PD-1 inhibition on cardiac function and explore the molecular mechanisms of ICI-induced cardiotoxicity. EXPERIMENTAL APPROACH: C57BL6/J and BALB/c mice were treated with isotype control or anti-PD-1 antibody. Echocardiography was used to assess cardiac function. Cardiac transcriptomic changes were investigated by bulk RNA sequencing. Inflammatory changes were assessed by qRT-PCR and immunohistochemistry in heart, thymus, and spleen of the animals. In follow-up experiments, anti-CD4 and anti-IL-17A antibodies were used along with PD-1 blockade in C57BL/6J mice. KEY RESULTS: Anti-PD-1 treatment led to cardiac dysfunction and left ventricular dilation in C57BL/6J mice, with increased nitrosative stress. Only mild inflammation was observed in the heart. However, PD-1 inhibition resulted in enhanced thymic inflammatory signalling, where Il17a increased most prominently. In BALB/c mice, cardiac dysfunction was not evident, and thymic inflammatory activation was more balanced. Inhibition of IL-17A prevented anti-PD-1-induced cardiac dysfunction in C57BL6/J mice. Comparing myocardial transcriptomic changes in C57BL/6J and BALB/c mice, differentially regulated genes (Dmd, Ass1, Chrm2, Nfkbia, Stat3, Gsk3b, Cxcl9, Fxyd2, and Ldb3) were revealed, related to cardiac structure, signalling, and inflammation. CONCLUSIONS: PD-1 blockade induces cardiac dysfunction in mice with increased IL-17 signalling in the thymus. Pharmacological inhibition of IL-17A treatment prevents ICI-induced cardiac dysfunction.
Gergely et al. (Thu,) conducted a other in Immune checkpoint inhibitor-induced cardiotoxicity. Anti-PD-1 antibody (with or without anti-IL-17A) vs. Isotype control was evaluated on Cardiac function and molecular mechanisms of ICI-induced cardiotoxicity. Anti-PD-1 treatment induced cardiac dysfunction and left ventricular dilation in C57BL/6J mice, which was prevented by pharmacological inhibition of IL-17A.
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