B cell depletion promotes melanoma tumor growth in a CD4+ T cell–dependent manner

B cells constitute ∼15% to 20% of tumor-infiltrating lymphocytes in melanoma. Their presence in the tumor microenvironment correlates with improved survival and enhanced response to immune checkpoint blockade therapy. Yet, the functional contribution of B cells to melanoma immunity remains unclear. In this study, we showed that both genetic and antibody-mediated B cell depletion significantly promoted melanoma progression in mice. Immune profiling revealed that, although B cell percentages were reduced, IL-10-producing B regulatory cells (Bregs) persisted after depletion. However, the persistence of Bregs alone cannot explain the impact of B cell depletion on enhancing melanoma growth, as codepletion of B cells and CD4+ T cells, despite similar Breg levels, did not promote melanoma progression. B cell depletion also resulted in the accumulation of PD-1+ B cells, CD4+ T cells, and monocytic myeloid-derived suppressor cells into the tumor microenvironment, alongside a reduction in IFN-γ+CD8+ T cells, CXCL13+CD8+ T cells, and M1-like macrophages. Notably, plasma cell deficiency did not affect tumor growth, indicating that B cell-mediated antitumor activity is independent of antibody production. The tumor-promoting effect of B cell loss was at least partially CD4+ T cell dependent, as codepletion of B cells and CD4+ T cells reversed this phenotype and B cell depletion did not enhance tumor growth in Nu/Nu mice lacking mature T cells. Taken together, our findings reveal an antitumor role of B cells in melanoma and demonstrate that their loss promotes tumor progression through reprogramming of the tumor immune microenvironment.