Metastatic malignant melanoma is highly resistant to chemotherapy, and the average survival rate is under 1 year.,The only FDA-approved conventional chemotherapy (i.e., dacarbazine) targets melanoma tumor cells by inducing a form of cell death referred to as apoptosis.,However, dacarbazine exhibits a response rate of ∼5%, and combination chemotherapies consisting of cisplatin, vinblastine, and dacarbazine often offer little clinical advantage over dacarbazine alone.,Apoptosis is governed by the BCL-2 family of proteins, which is comprised of anti-apoptotic and pro-apoptotic members.,To determine if the anti-apoptotic BCL-2 repertoire established the cell death threshold and chemoresistance in melanoma, a novel treatment strategy was designed to inhibit the anti-apoptotic BCL-2 members with ABT-737.,Using various melanoma model systems, we determined the affects of ABT-737 on sensitivity to dacarbazine-based regimens.,Strikingly, ABT-737 re-sensitized melanoma cell lines to common chemotherapeutics leading to marked BIM-mediated apoptosis.,Cellular features of the ABT-737 combination treatments were loss of proliferation, mitochondrial fragmentation, nuclear condensation, phosphatidylserine exposure, and decreased clonogenic survival.,We also observed significant anti-tumor activity in an in vivo melanoma model system.,Our data indicate that ABT-737 may be a beneficial adjuvant therapy to improve melanoma response rates when conventional chemotherapy is the only option.
Melanoma, a potentially lethal skin cancer, is widely thought to be immunogenic in nature.,While there has been much focus on T cell-mediated immune responses, limited knowledge exists on the role of mature B cells.,We describe an approach, including a cell-based ELISA, to evaluate mature IgG antibody responses to melanoma from human peripheral blood B cells.,We observed a significant increase in antibody responses from melanoma patients (n = 10) to primary and metastatic melanoma cells compared to healthy volunteers (n = 10) (P<0.0001).,Interestingly, we detected a significant reduction in antibody responses to melanoma with advancing disease stage in our patient cohort (n = 21) (P<0.0001).,Overall, 28% of melanoma patient-derived B cell cultures (n = 1,800) compared to 2% of cultures from healthy controls (n = 600) produced antibodies that recognized melanoma cells.,Lastly, a patient-derived melanoma-specific monoclonal antibody was selected for further study.,This antibody effectively killed melanoma cells in vitro via antibody-mediated cellular cytotoxicity.,These data demonstrate the presence of a mature systemic B cell response in melanoma patients, which is reduced with disease progression, adding to previous reports of tumor-reactive antibodies in patient sera, and suggesting the merit of future work to elucidate the clinical relevance of activating humoral immune responses to cancer.