Vaccination using melanoma cells treated with p19arf and interferon beta gene transfer in a mouse model: a novel combination for cancer immunotherapy
Abstract Previously, we combined p19Arf (Cdkn2a, tumor suppressor protein) and interferon beta (IFN b, immunomodulatory cytokine) gene transfer in order to enhance cell death in a murine model of melanoma. Here, we present evidence of the immune response induced when B16 cells succumbing to death due to treatment with p19Arf and IFN b are applied in vaccine models. Use of dying cells for prophylactic vaccination was investigated, identifying conditions for tumor free survival. After combined p19Arf and IFN b treatment, we observed immune rejection at the vaccine site in immune competent and nude mice with normal NK activity, but not in NOD SCID and dexamethasone immunosuppressed mice (NK deficient) Combined treatment induced IL 15, ULBP1, FAS/APO1 and KILLER/DR5 expression, providing a mechanism for NK activation. Prophylactic vaccination protected against tumor challenge, where markedly delayed progression and leukocyte infiltration were observed. Analysis of primed lymphocytes revealed secretion of TH1 related cytokines and depletion protocols showed that both CD4+ and CD8+ T lymphocytes are necessary for immune protection. However, application of this prophylactic vaccine where cells were treated either with IFN b alone or combined with p19Arf conferred similar immune protection and cytokine activation, yet only the combination was associated with increased overall survival. In a therapeutic vaccine protocol, only the combination was associated with reduced tumor progression. Our results indicate that by harnessing cell death in an immunogenic context, our p19Arf and IFN b combination offers a clear advantage when both genes are included in the vaccine and warrants further development as a novel immunotherapy for melanoma.
Cancer Immunology, Immunotherapy