Autor(es)

Vieira Medrano, Ruan Felipe ^[1] ; Portela Catani, Joao Paulo ^[1] ; Ribeiro, Aline Hunger ^[1] ; Tomaz, Samanta Lopes ^[2] ; Merkel, Christian A. ^[3] ; Costanzi-Strauss, Eugenia ^[4] ; Strauss, Bryan E. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Fac Med, Inst Canc Estado Sao Paulo, Viral Vector Lab, Ctr Invest Translac Oncol LIM24, Av Dr Arnaldo 251, 8th Floor, BR-01246000 Sao Paulo, SP - Brazil

^[2] Univ Fed Sao Paulo, Escola Paulista Med, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Fac Med, Anim Care Facil, Sao Paulo - Brazil

^[4] Univ Sao Paulo, Gene Therapy Lab, Inst Ciencias Biomed 1, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: CANCER IMMUNOLOGY IMMUNOTHERAPY; v. 65, n. 4, p. 371-382, APR 2016.
• Citações Web of Science: 9

Resumo

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. (AU)

• Processo FAPESP: 11/50911-4 - Elucidacao dos mecanismos moleculares que mediam a resposta da celulas de melanoma para a atividade combinada das vias de p53/arf e ifnb.
• Beneficiário: Bryan Eric Strauss
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 11/10656-5 - Avaliação dos mecanismos moleculares das vias de p53/ARF e IFN-beta envolvidos com a resposta de células de melanoma ao tratamento com os transgenes p19Arf e IFN-beta.
• Beneficiário: Aline Hunger Ribeiro
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 13/09474-5 - Associação da imunoterapia mediada pela transferência gênica de p19Arf e interferon-beta com morte imunogênica induzida pelo quimioterápico doxorrubicina para o tratamento do câncer
• Beneficiário: Ruan Felipe Vieira Medrano
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 14/11524-3 - Investigação dos mecanismos da resposta imune antitumoral induzida pela transferência gênica combinada de p19Arf e interferon-beta - ensaios em um modelo murino de câncer de pulmão
• Beneficiário: João Paulo Portela Catani
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 13/25167-5 - Transferência gênica de p19Arf e interferon-beta: delineando a importância de sua combinação em modelos murinos de terapia gênica do câncer
• Beneficiário: Bryan Eric Strauss
• Modalidade de apoio: Auxílio à Pesquisa - Regular