| Autor: |
Medrano RF; Viral Vector Laboratory, Centro de Investigação Translacional em Oncologia/LIM24, Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo, 251, 8th Floor, São Paulo, SP, 01246-000, Brazil., Catani JP; Viral Vector Laboratory, Centro de Investigação Translacional em Oncologia/LIM24, Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo, 251, 8th Floor, São Paulo, SP, 01246-000, Brazil., Ribeiro AH; Viral Vector Laboratory, Centro de Investigação Translacional em Oncologia/LIM24, Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo, 251, 8th Floor, São Paulo, SP, 01246-000, Brazil., Tomaz SL; Escola Paulista de Medicina-Universidade Federal de São Paulo, São Paulo, Brazil., Merkel CA; Animal Care Facility, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil., Costanzi-Strauss E; Gene Therapy Laboratory, Instituto de Ciências Biomédicas-I, Universidade de São Paulo, São Paulo, Brazil., Strauss BE; Viral Vector Laboratory, Centro de Investigação Translacional em Oncologia/LIM24, Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo, 251, 8th Floor, São Paulo, SP, 01246-000, Brazil. bstrauss@usp.br. |
| Abstrakt: |
Previously, we combined p19(Arf) (Cdkn2a, tumor suppressor protein) and interferon beta (IFN-β, 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-β 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-β 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-β 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-β 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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