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

心脏毒性 心肌炎 免疫系统 医学 心功能曲线 炎症 免疫检查点 免疫学 转录组 药理学 内科学 生物 免疫疗法 心力衰竭 基因表达 化疗 基因 生物化学
作者
Tamás G. Gergely,Dániel Kucsera,Viktória É. Tóth,Tamás Kovács,Nabil V. Sayour,Zsófia D. Drobni,Mihály Ruppert,Balázs Petrovich,Bence Ágg,Zsófia Onódi,Nóra Fekete,Éva Pállinger,Edit I. Buzás,Laura I. Yousif,Wouter C. Meijers,Tamás Radovits,Béla Merkely,Péter Ferdinandy,Zoltán V. Varga
出处
期刊:British Journal of Pharmacology [Wiley]
卷期号:180 (6): 740-761 被引量:43
标识
DOI:10.1111/bph.15984
摘要

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.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
han应助归华采纳,获得10
1秒前
1秒前
SYLH应助zly采纳,获得30
4秒前
完美世界应助娇气的天亦采纳,获得10
6秒前
8秒前
11秒前
科目三应助彭栋采纳,获得10
13秒前
方文浩发布了新的文献求助10
13秒前
ding应助YWang采纳,获得10
16秒前
16秒前
林宝雯关注了科研通微信公众号
21秒前
24秒前
斯文败类应助GGBOND采纳,获得10
24秒前
星辰大海应助科研通管家采纳,获得10
24秒前
李健的小迷弟应助GGBOND采纳,获得10
24秒前
上官若男应助科研通管家采纳,获得10
24秒前
25秒前
大模型应助科研通管家采纳,获得10
25秒前
圆锥香蕉应助科研通管家采纳,获得20
25秒前
星辰大海应助科研通管家采纳,获得10
25秒前
25秒前
25秒前
Bio应助科研通管家采纳,获得30
25秒前
科研通AI5应助科研通管家采纳,获得10
25秒前
斯文败类应助科研通管家采纳,获得10
25秒前
汉堡包应助科研通管家采纳,获得10
25秒前
26秒前
29秒前
31秒前
31秒前
Dotson发布了新的文献求助10
32秒前
sinsinsin发布了新的文献求助10
33秒前
CodeCraft应助娇气的天亦采纳,获得10
34秒前
35秒前
权思远发布了新的文献求助10
35秒前
彭栋发布了新的文献求助10
35秒前
量子星尘发布了新的文献求助10
36秒前
李爱国应助收集快乐采纳,获得10
37秒前
守墓人完成签到 ,获得积分10
38秒前
39秒前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
‘Unruly’ Children: Historical Fieldnotes and Learning Morality in a Taiwan Village (New Departures in Anthropology) 400
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
基于可调谐半导体激光吸收光谱技术泄漏气体检测系统的研究 350
Robot-supported joining of reinforcement textiles with one-sided sewing heads 320
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3989115
求助须知:如何正确求助?哪些是违规求助? 3531367
关于积分的说明 11253688
捐赠科研通 3269986
什么是DOI,文献DOI怎么找? 1804868
邀请新用户注册赠送积分活动 882078
科研通“疑难数据库(出版商)”最低求助积分说明 809105