부산대학교 도서관

Simple Summary: Immune checkpoint inhibitors (ICI) have the potential to induce serious and unpredictable immune-related adverse events (irAEs), the underlying mechanisms of which remain incompletely understood. In this study, we investigated the relationship between irAEs and the expression of IFN-inducible chemokines and cytokines in patients with solid tumours treated with PD-(L)1 inhibitors. We analysed plasma levels of various IFN-related cytokines at different time points in patients categorized by irAE development and severity. We found that patients with serious irAEs showed significant increases in CXCL9, CXCL10, CXCL11, IL-18 and IL-10 at the onset of the irAE compared to patients with mild irAEs and those without irAEs. Additionally, IL-18 emerged as a promising predictive biomarker for serious irAE development. In summary, this study provides valuable insights into the immune responses associated with irAEs and proposes potential predictive markers for their severity. 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. [ABSTRACT FROM AUTHOR]