Impact of patient ancestry on melanoma immunotherapy immune-related adverse events

Studies of racial differences in melanoma outcomes have mainly focused on disparity in social determinants of health, with limited understanding of the possible impact of different ancestry backgrounds. Herein, we assess whether ancestry-associated biological factors contribute to differences in immune-related adverse events (irAEs) in melanoma patients treated with immune checkpoint inhibitor (ICI) with comparable access to care. The study included melanoma patients who received ICIs at NYU Langone Health Perlmutter cancer Center. Ancestry was determined using whole genome sequencing (WGS). irAEs and treatment responses were compared between underrepresented minority (URM) and non-Hispanic white (NHW) patients. Serum autoantibody (autoAb) profiles were assessed using the KREX platform and analyzed for associations with irAEs. 841 patients were included in this study (774 NHW and 67 URM). Genetic testing revealed 98.7% agreement between self-reported and PCA-derived ancestry (AC1 = 0.99, 95% CI 0.97-1.00). Compared to NHW patients, in whom melanoma was more prevalent among males, melanoma in URM patients was significantly more common in females ( p = 0.03). Despite comparable melanoma stage, type of ICI treatment and treatment outcomes, URM patients experienced significantly more irAEs compared to NHW across all grades ( p < 0.001). URM patients’ sera displayed both overlapping and distinct autoAb profiles compared to NHW patients, with URM exhibiting a greater number of unique autoAbs. These autoAbs correlated with ICI-related toxicities. Pathway enrichment analysis identified autoAb targets involved in lymphocyte activation, immune signaling, and inflammatory regulation, consistent with heightened immune priming and distinct humoral immune recognition in URM patients experiencing irAEs. Our data support consideration of ancestry in clinical decision-making and risk stratification to improve the safety and effectiveness of ICIs in diverse patient populations.