Nectin-4 as predictive biomarker of immune-related adverse event subtypes in adjuvant anti-programmed-death-1 treatment of melanoma.

Immune checkpoint inhibitors have transformed melanoma management; however, immune-related adverse events (irAEs) remain a major source of morbidity. Soluble immunomodulatory proteins are established biomarkers of autoimmune reactivity but have not been validated as predictors of irAEs. Evaluating their associations with irAEs may help identify patients at elevated risk and inform optimization of adjuvant checkpoint inhibitor therapy. Baseline serum samples from patients with resectable melanoma receiving adjuvant anti-programmed-death-1 therapy were obtained from the University of Pittsburgh Melanoma Center biospecimen repository ( n  = 43). Soluble immunomodulatory proteins were quantified using Milliplex technology. Mean pretreatment protein levels were compared between patients with and without irAEs using two-sample t -tests. Siglec-7 and Siglec-9 were elevated in patients who developed any irAE. Dermatitis was associated with elevated B7-H3 and major histocompatibility complex class I polypeptides. Thyroiditis was associated with elevated Nectin-4 and CXCL13 and reduced LAG3. Colitis was associated with elevated arginase. Hepatitis was associated with increased Galectin-3 and decreased Galectin-1, CD40L, CD226, and Nectin-4. Nectin-4 remained significant after false discovery rate adjustment in both thyroiditis and hepatitis, and CD226 remained significant in hepatitis. Potential biomarkers of recurrence-free survival (perforin, CD25, and ICOSL) and overall survival (FGL1) were also identified. Baseline soluble immunomodulatory proteins may predict the development of specific irAEs and survival outcomes from adjuvant anti-programmed-death-1 treatment. Notably, Nectin-4 may serve as a biomarker for both thyroiditis and hepatitis. Prospective studies are warranted to validate these findings.