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Antibodies have been detected against known melanoma-associated antigens in patients with malignant disease. While much is known about cancer-specific T cell responses, the nature of cancer-specific B cells and their antibody repertoires are less well understood. We investigated circulating skin-homing B cells (CD19+CD22+CLA+) in healthy volunteers (n = 24) and melanoma patients (n = 49) and examined the presence of CD22+ B cells in melanoma lesions (n = 173) and normal skins tissue (n = 16). We detected mature IgG mRNA in 13 of 27 normal skin and 9 of 21 cutaneous melanoma samples and we detected mRNA for the enzyme Activation-induced cytidine deaminase (AID). IgG variable heavy chain sequences from melanomas (n = 51) and normal skins (n = 29) featured lower IgG1/IgGtotal subclass representation compared with circulating B cell antibody sequences (n = 36). The presence of affinity-matured cutaneous antibody repertoires in malignant skin was supported by evidence of somatic hypermutation, class-switching and B cell clonal family trees in melanoma lesions and a subset of melanoma-associated clones featuring shorter CDR3 region lengths relative to circulating B cell sequences. Homology modelling also indicated differential putative binding site patterns in melanoma compared to normal skin-resident antibodies, suggesting distinct melanoma-associated repertoires and potentially, antigen recognition profiles. These findings support the presence of a mature tumor-resident B cell compartment with characteristics distinct to that of B cells in normal skin and the circulation. Citation Format: Louise Saul, Kristina M. Ilieva, Heather J. Bax, Panagiotis Karagiannis, Isabel Correa, Irene Rodriguez-Hernandez, Debra H. Josephs, Isabella Tosi, Isioma U. Egbuniwe, Sara Lombardi, Silvia Crescioli, Carl Hobbs, Federica Villanova, Anthony Cheung, Jenny LC Geh, Ciaran Healy, Mark Harries, Victoria Sanz-Moreno, David Fear, James F. Spicer, Katie E. Lacy, Frank O. Nestle, Sophia N. Karagiannis. IgG antibody switching and clonal expansion in melanoma and normal skin microenvironments [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A116.