免疫检查点抑制剂诱导的心肌炎依赖于CD8 T细胞衍生TNF和TNFR2信号传递
Kathrynne A Warrick1,2,3,4, Anne Katrine Z Johansen3, Mengchi Jiao4,5
1Immunology Graduate Program, Cincinnati Children's Hospital Medical Center and University of Cincinnati , Cincinnati, OH, USA.
The Journal of experimental medicine
|February 20, 2026
概括
免疫检查点抑制剂 (ICI) 可以导致致命的心肌炎. 向T细胞衍生的TNF和TNFR2可以防止这种心脏自身免疫,同时保持癌症治疗的疗效.
科学领域:
- 免疫学 免疫学 免疫学
- 心脏病学 心脏病学
- 在瘤学瘤学.
背景情况:
- 免疫检查点抑制剂 (ICI) 增强抗癌免疫力,但可以诱导与免疫相关的不良事件,包括致命的心肌炎.
- 目前ICI诱导心肌炎的治疗方法有限,需要对其机制有更深入的了解.
研究的目的:
- 通过一种新的小鼠模型,阐明ICI引发心脏自身免疫的机制.
- 在不影响抗瘤效果的情况下,确定预防ICI诱导心肌炎的治疗点.
主要方法:
- 开发一种具有心肌细胞受限抗原表达的小鼠模型,以研究心脏自身免疫.
- 联合使用抗CTLA-4和抗PD-1阻断剂来诱导心肌炎.
- 评估T细胞反应,心肌炎症和心脏功能.
- 研究TNF和TNFR2在ICI诱导心脏毒性的作用.
主要成果:
- 结合ICI阻塞诱导了抗原特异性CD8 T细胞扩张,心肌炎症和致命性心律失常.
- 心肌损伤取决于T细胞衍生的TNF,而不是穿孔素介导的细胞毒性.
- TNF促进了髓状细胞的招募和细胞因子的产生,有助于心律失常.
- 对TNF或TNFR2阻断的基因切除可以预防心脏毒性,并保持抗瘤功效.
结论:
- 自主反应性CD8T细胞下游的TNF-TNFR2信号通路对于ICI心肌炎的发病过程至关重要.
- 针对这种TNF-TNFR2轴提供了一种策略,可以将心脏毒性与免疫治疗的好处分开.
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