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与检查点抑制剂诱导的心肌炎相关的致病性免疫细胞子组的鉴定

Han Zhu^1,2,3, Francisco X Galdos^2,4, Daniel Lee²

¹Department of Medicine (H.Z., S.W., J.W.N., H.A.W., S.A.R., S.S., R.M.W., P.K.N., S.M.W.), Stanford University, CA.

|June 28, 2022

概括

免疫检查点抑制剂 (ICI) 治疗可能导致心肌炎. 这项研究确定了重新表达CD45RA (Temra CD8+细胞) 的克隆细胞毒性T效应记忆细胞是ICI心肌炎的关键驱动因素,提供了潜在的诊断和治疗点.

科学领域:

免疫学
癌症学
心脏病学

背景情况:

免疫检查点抑制剂 (ICI) 激活免疫系统对抗癌症,但可能导致严重的心肌炎.
ICI心肌炎的特征是淋巴细胞透,表明T细胞参与,但具体的免疫子集仍然未知.

研究的目的:

确定与免疫检查点抑制剂 (ICI) 相关的特定免疫细胞子集和分子变化.
研究ICI心肌炎中外周血液免疫变化与心脏病理之间的相关性.

主要方法:

在ICI相关不良事件和健康对照患者的外周血液单核细胞上使用飞行时间质量细胞计和多组单细胞技术 (scRNA-seq,scTCR-seq,CITE-seq).
分析了自发性心肌炎的MRL/Pdcd1-/-小鼠的单细胞数据,以模拟人类疾病.
在小鼠模型中,与心脏病理相关的外周免疫特征.

主要成果:

在ICI心肌炎患者中发现了克隆扩张的细胞毒性CD8+T效应记忆细胞 (Temra CD8+细胞) 的扩张.
这些Temra CD8+细胞表现出高度活化的表型,具有高调的促炎化学因子 (CCL5,CCL4,CCL4L2),可能与先天免疫细胞相互作用.
在自发性心肌炎的小鼠血液和心脏组织中观察到类似的细胞毒性CD8+T细胞扩张.

结论:

在ICI心肌炎患者中,细胞扩张的Temra CD8+细胞显著增加,与小鼠模型中的发现相呼应.
这些细胞中CCL5/CCL4/CCL4L2化学激素的升级为ICI诱导的心脏不良事件的管理提供了潜在的诊断和治疗点.

关键词:

免疫检查点抑制剂免疫类型定型免疫疗法心肌炎单细胞分析

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