Here, by intracellular cytokine assays, multicolor flow, and cytometry by time of flight (CyTOF), immunohistochemistry/immunofluorescence (IHC/IF), ex vivo co-culture studies, coupled with single-cell RNA-seq and bulk gene expression data analyses, we investigated cytokine-expressing (TGF-β, IL-4, IL-10, IFN-γ, and TNF-α) B cells in the circulation of patients with melanoma and healthy volunteers, and in human melanoma lesions. The gene discussed is IFNG; the disease is melanoma.