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. 2023 Mar;180(6):740-761.
doi: 10.1111/bph.15984. Epub 2022 Dec 13.

Characterization of immune checkpoint inhibitor-induced cardiotoxicity reveals interleukin-17A as a driver of cardiac dysfunction after anti-PD-1 treatment

Tamás G Gergely  1   2   3 , Dániel Kucsera  1   2   3 , Viktória E Tóth  1   2   3 , Tamás Kovács  1   2   3 , Nabil V Sayour  1   2   3 , Zsófia D Drobni  4 , Mihály Ruppert  4 , Balázs Petrovich  1 , Bence Ágg  1   5   6 , Zsófia Onódi  1   2   3 , Nóra Fekete  7 , Éva Pállinger  7 , Edit I Buzás  7 , Laura I Yousif  8   9 , Wouter C Meijers  8   9 , Tamás Radovits  4 , Béla Merkely  4 , Péter Ferdinandy  1   5   6 , Zoltán V Varga  1   2   3
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Free article

Characterization of immune checkpoint inhibitor-induced cardiotoxicity reveals interleukin-17A as a driver of cardiac dysfunction after anti-PD-1 treatment

Tamás G Gergely et al. Br J Pharmacol. 2023 Mar.
Free article

Abstract

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.

Keywords: cancer immunotherapy; cardio-oncology; cardiotoxicity; heart failure; nivolumab; pembrolizumab.

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