Department of Oncology, the Second Medical Center of Chinese PLA General Hospital, 100853, Beijing, China.
Senior Department of Oncology, the Fifth Medical Center of PLA General Hospital, 100853, Beijing, China.
Oncogene. 2023 Oct;42(42):3098-3112. doi: 10.1038/s41388-023-02805-4. Epub 2023 Aug 31.
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.
检查点抑制剂性肺炎（CIP）是最常见的致命免疫相关不良事件；然而，其发病机制在很大程度上仍然未知。全面剖析与 CIP 发病机制相关的关键细胞因子和分子途径对于 CIP 的精准诊断和新型治疗策略的开发至关重要。在此，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）微环境中免疫反应的复杂性。CIP 的特征是 CXCL13+T 细胞和过度炎症性的 CXCL9+单核细胞的急剧积累。T 细胞受体（TCR）分析显示，CXCL13+T 细胞表现出过度扩张的 TCR 克隆型，而伪时间分析显示出从幼稚到细胞毒性效应状态的潜在分化轨迹。单核细胞轨迹显示，源自 CXCL9+单核细胞的 LAMP3+DC 具有从肿瘤迁移到 BALF 的潜力，而向抗炎性巨噬细胞的分化轨迹被阻断。细胞间串扰分析显示，CIP+样本中激活了 CXCL9/10/11-CXCR3、FASLG-FAS 和 IFNGR1/2-IFNG 等信号通路。我们还提出了一种具有高诊断能力的新型免疫特征，以区分 CIP+和 CIP-样本（AUC=0.755）。我们的数据突出了与 CIP 发病机制相关的关键细胞因子、特征和相互作用。
