Melanoma Response to Immunotherapy is regulated by B Cell-Derived Extracellular Vesicles

The immune tumor microenvironment (TME) is increasingly recognized as a dynamic ecosystem where B cells play pivotal roles in modulating therapeutic responses, particularly in the context of immune checkpoint blockade (ICB) therapy. While B cells have traditionally been viewed as bystanders in tumor immunity, recent evidence suggests they may actively influence anti-tumor immunity, albeit with conflicting reports regarding their pro-tumor or anti-tumor roles. This study explores the crucial roles played by B cells and their secreted extracellular vesicles (EVs) in shaping melanoma responses to ICB therapy. We show a significant enrichment of B cells in ICB therapy responders compared to non-responders, pre-treatment, through retrospective analyses of melanoma patient tumors. Functional assays demonstrate that B cell depletion impairs T cell-mediated tumor cytotoxicity, underscoring the importance of B cells in anti-tumor responses. To investigate the clinical relevance, EVs were isolated from melanoma patient tumors, and fractioned into tumor and immune subpopulations. MiRNA profiling of CD19+ EVs identifies miR-99a-5p as a top candidate, among several others, upregulated in responders. Functional assays show that miR-99a-5p silencing in B cells diminishes T cell-mediated anti-tumor activity, suggesting its role in promoting B cell-mediated immune responses. Mechanistically, miR-99a-5p influences B cell maturation within the TME by mediating class-switch recombination. Our findings highlight the important role of B cells and their derived EVs in shaping the efficacy of melanoma immunotherapy, paving the way for novel therapeutic strategies targeting B cell-related pathways. Graphical abstract (created with Biorender) O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=177 SRC="FIGDIR/small/628150v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@144bbe6org.highwire.dtl.DTLVardef@18c1e9eorg.highwire.dtl.DTLVardef@2e37aaorg.highwire.dtl.DTLVardef@487e18_HPS_FORMAT_FIGEXP M_FIG C_FIG