Blood parameters and whole-blood transcriptomics associated with immune-related adverse events in metastatic renal cell carcinoma during nivolumab plus ipilimumab.

Pretreatment immune profiles associated with immune-related adverse events (irAEs) may inform individualized management strategies, including enhanced monitoring and early toxicity intervention, in patients with metastatic renal cell carcinoma (mRCC) treated with nivolumab plus ipilimumab. In this cohort (n = 51), we analyzed pretreatment peripheral blood parameters and whole-blood transcriptomic profiles. Higher lymphocyte and monocyte counts (odds ratios [ORs] 14.36 and 9.90, respectively) were significantly associated with an increased risk of irAEs, whereas higher neutrophil counts and C-reactive protein levels (ORs 0.08 and 0.27, respectively) were associated with a decreased risk. To characterize immune pathways associated with irAE development, we performed whole-blood transcriptomic analyses. Gene set enrichment analysis revealed upregulation of lymphocyte- and humoral immunity-related pathways and downregulation of neutrophil- and inflammatory-related pathways in patients who developed irAEs. CIBERSORTx demonstrated reduced neutrophil fractions and increased proportions of CD8⁺ T cells and activated memory CD4⁺ T cells, indicating an adaptive immune-dominant profile. Exploratory analysis identified five candidate genes (ANAPC1, CDK4, MCM6, GRAP2, and BST2) that may contribute to the immune features associated with irAE development. Collectively, these findings suggest that irAE development is associated with a distinct systemic immune profile characterized by enhanced lymphocyte-related and reduced neutrophil-related immune activity.