B cells and humoral immunity in melanoma: regulatory and autoimmune-like features and implications for immunotherapy.

Abstract

B cells and the humoral immune response are increasingly recognized as critical modulators of melanoma progression and immunotherapy outcomes. While checkpoint inhibitor (CPI) therapy was developed to target T cell exhaustion mechanisms, emerging evidence highlights the complexity and clinical relevance of B cell biology in this highly immunogenic cancer. Dysregulated B cell subsets, including enriched circulating naïve and immunosuppressive populations, and skewing toward immune-inert antibody isotypes such as IgG4, correlate with diminished Fc-mediated effector functions and poor survival. Regulatory B cells (Bregs) contribute to immune tolerance by inducing regulatory T cells (Tregs) and shaping the suppressive tumor microenvironment (TME) via the secretion of immunosuppressive cytokines (TGFβ and IL-10). While intratumoral B cells exhibit clonal expansion, somatic hypermutation, and polyreactivity, the expression of antibodies with high frequencies of unproductive sequences may support an active yet aberrant autoimmune-like humoral response. Conversely, mature class-switched memory B cells and tumor-resident B cell populations, including those assembled in tertiary lymphoid structures (TLSs), are associated with improved CPI responses. Dynamic changes in circulating B cell phenotypes and autoantibody profiles during CPI treatment further link humoral immunity to therapeutic efficacy and immune-related adverse events (irAEs). Collectively, these findings underscore a dual role for B cells in melanoma, supporting antitumor immunity or promoting immune escape, and highlight opportunities to target Bregs, correct isotype imbalance, and leverage B cell signatures as biomarkers. Monitoring humoral responses before and during CPI therapy may inform patient stratification, predict toxicity, and guide interventions to optimize immunotherapy outcomes.