抑制剂肺炎（CIP）是最常见的致命免疫相关不良事件；然而，其病理生理机制仍然大部分不明。全面解剖与CIP病理生物学相关的关键细胞因子和分子途径对于精确诊断和开发CIP新疗法非常关键。在本研究中，我们进行了全面的单细胞转录组分析，以剖析支气管肺泡灌洗液（BALF）微环境中的免疫反应复杂性。CIP的特征是CXCL13+ T细胞和高炎症性CXCL9+单核细胞的显著积聚。T细胞受体（TCR）分析显示，CXCL13+ T细胞表现出超扩增的TCR克隆型，并且伪时间分析显示从初级到细胞毒性效应状态的潜在分化轨迹。单核细胞分化轨迹显示从CXCL9+单核细胞衍生的LAMP3+ DCs具有从肿瘤迁移到BALF的潜力，而向抗炎巨噬细胞的分化轨迹被阻断。细胞间相互作用分析揭示了在CIP+样本中激活的信号途径，如CXCL9/10/11-CXCR3，FASLG-FAS和IFNGR1/2-IFNG。我们还提出了一种新的免疫特征，具有高诊断能力，可以将CIP+样本与CIP-样本区分开来（AUC = 0.755）。我们的数据突出了CIP发病机制所涉及的关键细胞因子、特征和相互作用。 © 2023. 作者。

Checkpoint inhibitor pneumonitis (CIP) is the most common fatal immune-related adverse event; however, its pathophysiology remains largely unknown. Comprehensively dissecting the key cellular players and molecular pathways associated with CIP pathobiology is critical for precision diagnosis and develop novel therapy strategy of CIP. Herein, we performed a comprehensive single-cell transcriptome analysis to dissect the complexity of the immunological response in the bronchoalveolar lavage fluid (BALF) microenvironment. CIP was characterized by a dramatic accumulation of CXCL13+ T cells and hyperinflammatory CXCL9+ monocytes. T-cell receptor (TCR) analysis revealed that CXCL13+ T cells exhibited hyperexpanded- TCR clonotypes, and pseudotime analysis revealed a potential differentiation trajectory from naïve to cytotoxic effector status. Monocyte trajectories showed that LAMP3+ DCs derived from CXCL9+ monocytes possessed the potential to migrate from tumors to the BALF, whereas the differentiation trajectory to anti-inflammatory macrophages was blocked. Intercellular crosstalk analysis revealed the signaling pathways such as CXCL9/10/11-CXCR3, FASLG-FAS, and IFNGR1/2-IFNG were activated in CIP+ samples. We also proposed a novel immune signature with high diagnostic power to distinguish CIP+ from CIP- samples (AUC = 0.755). Our data highlighted key cellular players, signatures, and interactions involved in CIP pathogenesis.© 2023. The Author(s).