ObjectiveThis study aimed to explore the shared mechanisms and targets between immune checkpoint inhibitor-associated myocarditis (ICIM) and autoimmune myocarditis.MethodsRelevant data were retrieved from public datasets and Gene Expression Omnibus (GEO) database. Gene set enrichment analysis (GSEA) of differentially expressed genes (DEGs) was used to identify significant shared signaling pathways between ICIM and non-ICI associated autoimmune myocarditis (NICIAM) represented by ICIM model and experimental autoimmune myocarditis (EAM) model, respectively. Cell type enrichment analysis and immune infiltration analysis by clusterProfiler and ImmuCellAI were performed to identify critical immune cell component involved in ICIM and NICIAM. Additionally, core shared genes across ICIM and NICIAM were identified and validated by various models and methods.ResultsInterferon-γ response, inflammatory response and allograft rejection signaling were identified as the shared signaling pathways associated with ICIM and NICIAM. Enrichment analysis of cell type supported an important role of increased infiltration of T cells and macrophages in both ICIM and NICIAM. However, the predominant increase of infiltrated T cells was CD4+ T cells in NICIAM, while that were CD8+ T cells in ICIM. Core shared genes Lck and Cd3d expression were found increased in both ICIM and NICIAM, and Lck inhibition was further identified and validated as potential therapeutic approach.ConclusionsOur study initially established a comorbidity model to identify potential molecular mechanism including interferon-γ response, inflammatory response and allograft rejection signaling accounting for the concerns of myocarditis risk in patients with preexisting autoimmune disease (PAD) receiving ICI treatment, and supported the therapeutic potential of targeting Lck or Cd3d.

中文翻译：

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免疫检查点抑制剂相关性心肌炎与自身免疫性心肌炎的共同机制和靶点的鉴定

目的探讨免疫检查点抑制剂相关性心肌炎（ICIM）与自身免疫性心肌炎的共同机制和靶点。方法从公共数据集和基因表达综合（GEO）数据库中检索相关数据。使用差异表达基因（DEG）的基因集富集分析（GSEA）来识别分别以ICIM模型和实验性自身免疫性心肌炎（EAM）模型为代表的ICIM和非ICI相关自身免疫性心肌炎（NICIAM）之间显着共享的信号通路。通过 clusterProfiler 和 ImmuCellAI 进行细胞类型富集分析和免疫浸润分析，以确定参与 ICIM 和 NICIAM 的关键免疫细胞成分。此外，通过各种模型和方法鉴定和验证了ICIM和NICIAM的核心共享基因。结果干扰素-γ反应、炎症反应和同种异体移植排斥信号被确定为与ICIM和NICIAM相关的共享信号通路。细胞类型的富集分析支持了 ICIM 和 NICIAM 中 T 细胞和巨噬细胞浸润增加的重要作用。然而，NICIAM 中浸润性 T 细胞的主要增加是 CD4+ T 细胞，而 ICIM 中主要是 CD8+ T 细胞。核心共享基因 Lck 和 Cd3d 表达在 ICIM 和 NICIAM 中均有所增加，并且 Lck 抑制被进一步鉴定和验证为潜在的治疗方法。同种异体移植排斥信号传导解释了接受 ICI 治疗的既往自身免疫性疾病 (PAD) 患者的心肌炎风险，并支持了靶向 Lck 或 Cd3d 的治疗潜力。