Intratumoral Immunization by p19Arf and Interferon-beta Gene Transfer in a Heterotopic Mouse Model of Lung Carcinoma

Autor(es)

Portela Catani, Joao Paulo ; Medrano, Ruan F. V. ; Hunger, Aline ; Del Valle, Paulo ; Adjemian, Sandy ; Zanatta, Daniela Bertolini ; Kroemer, Guido ; Costanzi-Strauss, Eugenia ; Strauss, Bryan E.

• Tipo de documento: Artigo Científico
• Fonte: TRANSLATIONAL ONCOLOGY; v. 9, n. 6, p. 565-574, DEC 2016.
• Citações Web of Science: 8

Resumo

Therapeutic strategies that act by eliciting and enhancing antitumor immunity have been clinically validated as an effective treatment modality but may benefit from the induction of both cell death and immune activation as primary stimuli. Using our AdRGD-PG adenovector platform, we show here for the first time that in situ gene transfer of p19Arf and interferon-beta (IFN beta) in the LLC1 mouse model of lung carcinoma acts as an immunotherapy. Although p19Arf is sufficient to induce cell death, only its pairing with IFN beta significantly inducedmarkers of immunogenic cell death. In situ gene therapy with IFN beta, either alone or in combination with p19Arf, could retard tumor progression, but only the combined treatment was associated with a protective immune response. Specifically in the case of combined intratumoral gene transfer, we identified 167 differentially expressed genes when usingmicroarray to evaluate tumors that were treated in vivo and confirmed the activation of CCL3, CXCL3, IL1 alpha, IL1 beta, CD274, and OSM, involved in immune response and chemotaxis. Histologic evaluation revealed significant tumor infiltration by neutrophils, whereas functional depletion of granulocytes ablated the antitumor effect of our approach. The association of in situ gene therapy with cisplatin resulted in synergistic elimination of tumor progression. In all, in situ gene transfer with p19Arf and IFN beta acts as an immunotherapy involving recruitment of neutrophils, a desirable but previously untested outcome, and this approach may be allied with chemotherapy, thus providing significant antitumor activity and warranting further development for the treatment of lung carcinoma. (AU)

• 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: 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: 12/25380-8 - Análise da expressão gênica global regulada pelo complexo prame/ezh2 como ferramenta para descoberta de novos alvos terapêuticos contra o câncer
• Beneficiário: Sandy Adjemian Portela Catani
• Modalidade de apoio: Bolsas no Brasil - Pós-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