致病性心脏巨细胞在免疫检查点抑制剂心肌炎中的扩张
1Cardiovascular Division, Department of Medicine (P.M., J.L., A.B., G.B., G.F., J.J., R.H., A.P., J.A., K.J.L.), Washington University School of Medicine, St Louis, MO.
Circulation
|September 25, 2023
概括
免疫检查点抑制剂 (ICI) 心肌炎涉及特定的炎症性巨细胞. 阻断干扰素- (IFN-γ) 信号可能为这种疾病提供新的治疗策略.
科学领域:
- 免疫学
- 心脏病学
- 癌症学
背景情况:
- 免疫检查点抑制剂 (ICI) 彻底改变了癌症治疗,但可能导致严重的免疫相关不良事件,特别是心肌炎.
- ICI心肌炎经常与PD- 1和CTLA- 4联合抑制有关,其特征是T细胞和巨细胞透到心脏.
- 在ICI心肌炎中透性巨细胞的具体作用和特征在很大程度上是未知的.
研究的目的:
- 在ICI心肌炎的小鼠模型中研究心脏免疫细胞,特别是巨细胞的身份,多样性和功能.
- 阐明ICI心肌炎发病过程中T细胞和巨细胞相互作用的机制.
主要方法:
- 使用ICI心肌炎的小鼠模型 (Ctla4Pdcd1小鼠).
- 采用单细胞RNA测序,免疫染色,流细胞测量,局部RNA杂交,分子成像和抗体中和.
- 使用in silico预测分析了细胞间的通信.
主要成果:
- 在小鼠ICI心肌炎模型中发现了CCR2+单细胞衍生的巨细胞和CD8+T细胞的扩张.
- 在表达CXCL9,CXCL10,GBP2B和FCGR4的炎症性CCR2+亚群中丰富的异质巨体区,来自CCR2+单细胞.
- 在人类ICI心肌炎患者中观察到类似的巨细胞群 (CXCL9+,CXCL10+,CD16α+).
- 通过IFN-γ/CXCR3信号的T细胞和巨细胞相互作用对于疾病的发病至关重要,这是治疗干预的证据.
结论:
- ICI心肌炎与IFN-γ诱导的炎症性巨细胞的一个特定群体的扩张有关.
- 这些发现表明,针对IFN-γ信号可能是ICI心肌炎的潜在治疗策略.
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