While tumor-reactive antibodies were detected from most melanoma patients studied, antibody responses derived from circulating B cells against melanoma cells decreased with more advanced disease stages (Figure 3 ). Previous serological studies report serum-resident antibodies against tumor cells in melanoma patients, with some evidence that serum antibodies are diminished in patients with advanced disease [25, 47] . It was unclear whether this was a consequence of the sequestering of antibodies into tumors with increasing tumor burden in these patients. Our findings provide further insight by demonstrating the presence of a circulating long-term mature B cell response to cancer at all disease stages, against a broad range of naturally expressed antigens on the surface of primary and metastatic tumor cells. We also report decreased frequency of tumorreactive antibody-producing B cells with advanced disease, thus supporting the premise that mechanisms of immune tolerance rather than adsorption of antibodies into tumors in advanced disease setting may also explain these reductions. One limitation may arise from screening for antibodies against mostly metastatic melanoma cells. It is possible that our observations may reflect reactivity to antigens present in primary disease, which may be preserved or upregulated in advanced disease setting. While our findings may not account for reactivity to tumor antigens that are lost with disease progression, this reduced reactivity to melanoma we observed may imply weakened immune responses to a subset of antigens on the surface of melanoma cells. Another explanation for these observations may be that with advanced disease, mature circulating B cells home into increasing tumor sites, thus reducing the circulating tumor-reactive B cell compartment in these patients. Future studies aimed at monitoring local B cell responses in tumors may provide further clues into the dynamics of mature B cell responses at the systemic and local levels in cancer. Thus, despite well-known weakened host immune response with disease progression [48] , we were able to detect melanoma-reactive antibodies from patient circulating B cells, implying that although mature humoral immune responses are weakened, responses in the form of mature memory B cells may persist. However, further work elucidating potential immunomodulatory roles of B cells and other immune cells in cancer, including the production of IL-10 by B cell population subsets [49] , merits consideration.