免疫检查点抑制剂诱导的心脏毒性的特征分析揭示了白细胞介素-17A 是抗 PD-1 治疗后心脏功能障碍的驱动因素。

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

机构信息

Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.

HCEMM-SE Cardiometabolic Immunology Research Group, Semmelweis University, Budapest, Hungary.

出版信息

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

DOI:10.1111/bph.15984

PMID:36356191

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.

摘要

背景与目的

免疫检查点抑制剂（ICI），如抗 PD-1 单克隆抗体，通过增强 T 细胞对肿瘤的细胞毒性作用，彻底改变了癌症治疗。然而，增强的 T 细胞活性也可能导致心肌炎和心脏毒性。我们对 ICI 诱导的心脏毒性的机制的理解是有限的。在这里，我们旨在研究 PD-1 抑制对心脏功能的影响，并探索 ICI 诱导的心脏毒性的分子机制。

实验方法

用同种型对照或抗 PD-1 抗体处理 C57BL6/J 和 BALB/c 小鼠。使用超声心动图评估心脏功能。通过 bulk RNA 测序研究心脏转录组的变化。通过 qRT-PCR 和免疫组化评估动物心脏、胸腺和脾脏的炎症变化。在后续实验中，在 C57BL/6J 小鼠中使用抗 CD4 和抗 IL-17A 抗体与 PD-1 阻断联合使用。

主要结果

抗 PD-1 治疗导致 C57BL/6J 小鼠心脏功能障碍和左心室扩张，并伴有硝化应激增加。心脏仅观察到轻度炎症。然而，PD-1 抑制导致胸腺炎症信号增强，其中 Il17a 增加最明显。在 BALB/c 小鼠中，没有明显的心脏功能障碍，胸腺炎症激活更为平衡。抑制 IL-17A 可预防 C57BL6/J 小鼠抗 PD-1 诱导的心脏功能障碍。比较 C57BL/6J 和 BALB/c 小鼠的心肌转录组变化，揭示了差异调节基因（Dmd、Ass1、Chrm2、Nfkbia、Stat3、Gsk3b、Cxcl9、Fxyd2 和 Ldb3），与心脏结构、信号和炎症有关。