Olink Platform-Based Identification of Peripheral Blood Biomarkers for irAEs in Advanced NSCLC

Lung cancer is the leading cause of cancer-related mortality worldwide. Immunotherapy has transformed the treatment landscape for advanced non-small cell lung cancer (NSCLC). However, immune-related adverse events (irAEs) represent a major clinical challenge during immunotherapy. These events can affect any organ system, and severe irAEs may necessitate treatment interruption or lead to life-threatening outcomes. We prospectively enrolled 84 advanced NSCLC patients treated with immunotherapy (June 2022-June 2024, followed until February 2025), including 57 who developed grade 1-4 irAEs and 27 who did not. Peripheral blood was collected from 39 patients at baseline for Olink platform-based proteomic screening, complemented by flow cytometric analysis of lymphocyte subsets. Olink profiling revealed IL13 and TRAIL as the most significantly differentially expressed proteins between irAEs and non-irAE groups. These proteins were enriched in biological processes such as negative regulation of lung ciliated cell differentiation and positive regulation of lung goblet cell differentiation, as well as in asthma and inflammatory bowel disease pathways. Moreover, dynamic changes in total T lymphocytes, T helper cells, NK cells, and the CD4/CD8 ratio were strongly associated with irAE occurrence. These markers, readily measurable in peripheral blood, offer potential for early risk stratification and real-time monitoring.