Phenotypic, functional, prognostic and predictive significance of B-cell and antibody responses in human melanoma: a scoping review

BACKGROUND: The clinical significance of B cells and the antibodies they express is increasingly appreciated in melanoma, a highly immunogenic tumour, for which immune checkpoint inhibitor (ICI) therapy is the standard care for advanced disease. OBJECTIVES: To evaluate the phenotypes and roles of B cells and antibodies in patients with melanoma, and their prognostic and predictive value, in a scoping review following PRISMA-ScR reporting guidelines. METHODS: Using three search engines, we conducted literature searches for full-text studies written in English from 1 January 2000 to 9 October 2024. Three reviewers conducted title and abstract screening, followed by full-text paper assessment by two independent reviewers. This study was registered with PROSPERO (CRD42024592965). RESULTS: Of 4667 identified studies (PubMed, n = 827; Scopus, n = 2759; Ovid MEDLINE, n = 1081), 1659 were duplicates. The titles and abstracts of the remaining 3008 were screened to yield 251 full-text papers, resulting in the inclusion of 80 studies. Our search identified increased naïve, alternatively activated and regulatory B cells in blood, and a bias towards differentiated and class-switched B-cell infiltrates in tumours. Consistent associations were found between B-cell density in tumours, particularly the abundance of memory B cells and more favourable survival outcomes. Despite tumour and immune response heterogeneity, collectively, enriched B-cell signatures such as B-cell abundance, B-cell receptor diversity and immunoglobulin gene rearrangement in tumours correlated with better ICI response. Antibody dysregulation favouring the anti-inflammatory IgG4 isotype was associated with less-favourable outcomes, while class switching to immune-stimulating isotypes such as IgG1 correlated with better clinical outcomes and ICI response. Antibody reactivity and autoantibody analysis revealed distinct isotype signatures in patients, the presence of cancer antigen-reactive antibodies and an association between increased autoantibody production on treatment with ICIs and the development of toxicity (immune-related adverse events; irAEs). CONCLUSIONS: We draw consensus for associations between class-switched B cells and immune-active antibody isotypes that indicate heightened classical immunity, with improved immunotherapy response. Alternatively activated, regulatory B cells and immune-inert antibody isotypes are associated with immunosuppression and less-favourable clinical outcomes. We reveal aspects of humoral immunity that offer opportunities to identify predictive biomarkers of immunotherapy response and irAEs.