Vaccine-expanded plasmablast-like B cells are associated with response to dendritic cell therapy in metastatic melanoma

Background: Dendritic Cell Vaccines (DCVax) can induce tumor-specific immune responses, yet their clinical activity remains limited and poorly understood. We sought to identify cellular and molecular features within the vaccine product that are associated with clinical response to monocyte-derived DC vaccines in metastatic melanoma. Methods: We performed a multi-omics analysis integrating multiparametric flow cytometry, single-cell RNA sequencing of DCVax products, transcriptomic profiling of CD14⁺ monocytes from apheresis, and in situ characterization of pre-treatment melanoma biopsies. Patients were stratified into Responders (Rs) or Non-Responders (NRs) based on best overall response and Delayed-Type Hypersensitivity (DTH) status. Results: An unanticipated population of CD19⁺ plasmablast-like B cells was identified within the final DCVax products. These B cells, phenotypically distinct from their circulating precursors, were significantly enriched in Rs and mirrored a B-cell-inflamed baseline state characterized by mature Tertiary Lymphoid Structures (mTLS) in pre-treatment tumor lesions. While mature LAMP3⁺ DCs appeared at comparable frequencies across outcomes, LAMP3⁺ DCs from Rs selectively upregulated HSPA1A/B, consistent with enhanced antigen-processing programs. Transcriptomic signatures of antibody production in vaccine-resident B cells, together with Fc receptor expression on DCs, support a model in which B-cell activity may contribute to antigen loading and DC functional tuning during vaccine manufacturing, a hypothesis that warrants functional validation. Conclusions: Our findings reveal a previously unrecognized B-cell component of DCVax biology, suggesting that cooperative DC-B-cell interactions, combined with baseline B-cell/mTLS features, may contribute to shaping vaccine immunogenicity. While causality cannot be established from the present data, these insights offer actionable avenues for enhancing both vaccine manufacturing and patient selection, extending beyond melanoma.