Journal
CANCER IMMUNOLOGY IMMUNOTHERAPY
Volume 65, Issue 4, Pages 371-382Publisher
SPRINGER
DOI: 10.1007/s00262-016-1807-8
Keywords
Cell death; p19Arf; Interferon beta; Immunotherapy; Melanoma; Adenovirus
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Funding
- Sao Paulo Research Foundation [13/25167-5, 11/50911-4, 13/09474-5, 11/10656-5, 14/11524-3]
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [13/25167-5, 14/11524-3, 11/10656-5, 13/09474-5] Funding Source: FAPESP
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Previously, we combined p19(Arf) (Cdkn2a, tumor suppressor protein) and interferon beta (IFN-beta, 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 p19(Arf) and IFN-beta are applied in vaccine models. Use of dying cells for prophylactic vaccination was investigated, identifying conditions for tumor-free survival. After combined p19(Arf) and IFN-beta 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-beta alone or combined with p19(Arf) 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 p19(Arf) and IFN-beta combination offers a clear advantage when both genes are included in the vaccine and warrants further development as a novel immunotherapy for melanoma.
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