Background: We recently reported that a pretreatment autoantibody (AutoAb) signature predicts immune-related adverse events (irAE) with an AUC of ~0.80 in melanoma patients enrolled in two phase III clinical trials of adjuvant ICI (Johannet et al. CCR 2022). The vast majority of those patients were non-Hispanic whites (NHW). We hypothesized that underrepresented minority (URM) melanoma patients might have a different baseline autoAb profile compared to NHW patients, as their site-specific irAEs differ (Xue Baiet al. Br J of Derm 2022) and autoimmune disease is generally more common in underrepresented minorities (Roberts MH, Erdei E. Autoimmune Review 2020). We also explored the possibility that differences in the immuno-biology of acral melanoma (AM) and cutaneous melanoma (CM) – most commonly detected in URM and NHW patients, respectively – might inform our understanding of the racial differences in irAEs. Methods: We compared pre-treatment sera autoAb from URM melanoma patients (n=35) to NHW patients (n= 185) enrolled in Checkmate-238 (NCT02388906), Checkmate-915 (NCT03068455) or the NYU melanoma program database using the CDI and Sengenics proteomic platforms, and analyzed their association(s) with the development of grade 3-4 irAEs. We carried out single cell RNA-seq in AM versus CM tumor tissues to test whether expression of genes whose proteins were associated with irAE were preferentially expressed in AM tissue. We also compared RNA-seq of an immunoregulatory gene panel in AM versus CM tumors. Results: We identified autoAbs that were only detected in sera from URM patients with grade 3-4 irAEs (e.g. ALDOA, BANK1, LDHB and RNF7) and autoAbs that were only detected in NHW patients with grade 3-4 irAEs (e.g. GMEB2, YWHAE and ANKRD45). A subset of these autoAb targets was preferentially expressed in AM or CM tissues, while other targets were undetected in these melanoma subtypes. Cytokine signaling pathways were enriched in sera from URM but not NHW patients, and expression of genes known to modulate irAEs and response to ICI were significantly more expressed in AM than CM tumors, e.g. FOXP3 (P=0.01), IL2 (P=0.00547), IL4 (P=0.0221) and IL10 (P=0.0126). Conclusions: Our data suggest that URM patients have an altered tumor immune microenvironment that defines their response to ICI and risk of developing irAE. An integrative analysis of both the tumor and systemic immune environments is needed to better understand molecular links between response to ICI and irAEs in URM and NHW melanoma patients. A multi-center study is planned to address these questions.