Immune checkpoint inhibitors (ICI) have the potential to trigger unpredictable immune-related adverse events (irAEs), which can be severe. The underlying mechanisms of these events are not fully understood. As PD-L1 is upregulated by IFN, the heightened immune activation resulting from PD-1/PD-L1 inhibition may enhance the IFN response, triggering the expression of IFN-inducible genes and contributing to irAE development and its severity. In this study, we investigated the interplay between irAEs and the expression of IFN-inducible chemokines and cytokines in 134 consecutive patients with solid tumours treated with PD-(L)1 inhibitors as monotherapy or in combination with chemotherapy or other immunotherapy agents. We compared the plasma levels of IFN-associated cytokines (CXCL9/10/11, IL-18, IL-10, IL-6 and TGFβ) at various time points (at baseline, at the onset of irAE and previous to irAE onset) in three patient groups categorized by irAE development and severity: patients with serious irAEs, mild irAEs and without irAEs after PD-(L)1 inhibitors. No differences were observed between groups at baseline. However, patients with serious irAEs exhibited significant increases in CXCL9/10/11, IL-18 and IL-10 levels at the onset of the irAE compared to baseline. A network analysis and correlation patterns highlighted a robust relationship among these chemokines and cytokines at serious-irAE onset. Combining all of the analysed proteins in a cluster analysis, we identified a subgroup of patients with a higher incidence of serious irAEs affecting different organs or systems. Finally, an ROC analysis and a decision tree model proposed IL-18 levels ≥ 807 pg/mL and TGFβ levels ≤ 114 pg/mL as predictors for serious irAEs in 90% of cases. In conclusion, our study elucidates the dynamic changes in cytokine profiles associated with serious irAE development during treatment with PD-(L)1 inhibitors. The study’s findings offer valuable insights into the intricate IFN-induced immune responses associated with irAEs and propose potential predictive markers for their severity.
免疫检查点抑制剂（ICI）可能引发不可预测且可能严重的免疫相关不良事件（irAEs），其发生机制尚未完全阐明。由于PD-L1受IFN上调，PD-1/PD-L1抑制导致的免疫激活增强可能放大IFN反应，进而诱导IFN诱导基因表达，促进irAE发生并影响其严重程度。本研究连续纳入134例接受PD-(L)1抑制剂单药或联合化疗/其他免疫治疗的实体瘤患者，探讨irAEs与IFN诱导趋化因子及细胞因子表达的关联。根据irAE发生情况及严重程度将患者分为三组（严重irAE组、轻度irAE组、无irAE组），比较各组在基线期、irAE发生时及发生前不同时间点血浆IFN相关细胞因子（CXCL9/10/11、IL-18、IL-10、IL-6和TGFβ）水平。基线期各组间无显著差异，但严重irAE组在irAE发生时较基线期CXCL9/10/11、IL-18及IL-10水平显著升高。网络分析与相关性模式显示这些趋化因子和细胞因子在严重irAE发生时存在强关联。通过聚类分析整合所有检测蛋白，我们识别出一个具有更高多器官/系统严重irAE发生率的患者亚群。ROC分析与决策树模型提示，IL-18水平≥807 pg/mL且TGFβ水平≤114 pg/mL可预测90%的严重irAE病例。本研究系统阐明了PD-(L)1抑制剂治疗期间严重irAE发生相关的细胞因子谱动态变化，为理解irAE相关的复杂IFN诱导免疫应答提供了重要依据，并提出了潜在的严重程度预测标志物。
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