Reestablishment of p53/Arf and interferon-β pathways mediated by a novel adenoviral vector potentiates antiviral response and immunogenic cell death

Hunger, Aline; Medrano, Ruan F.V.; Zanatta, Daniela B; Valle, Paulo Roberto Del; Merkel, Christian; Salles, Thiago A.; Ferrari, Daniel Gomes; Furuya, Tatiane Katsue; Bustos, Silvina Odete; Saito, Renata de Freitas; Strauss, Bryan E.

doi:10.1038/cddiscovery.2017.17

Cited by 30 publications

(53 citation statements)

References 47 publications

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“…Growth arrest causes a temporary arrest of cell cycle progression, enabling the cell to correct damaged DNA, and prevent the replication of damaged DNA and the transfer of the genetic aberrations to daughter cells. In addition to inducing cell cycle arrest, p53 also promotes DNA repair [14][15][16][17]. Once DNA repair is complete, the cell cycle resumes.…”

Section: Introductionmentioning

confidence: 99%

Do Mutations Turn p53 into an Oncogene?

Pitolli

Wang

Mancini

et al. 2019

IJMS

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The key role of p53 as a tumor suppressor became clear when it was realized that this gene is mutated in 50% of human sporadic cancers, and germline mutations expose carriers to cancer risk throughout their lifespan. Mutations in this gene not only abolish the tumor suppressive functions of p53, but also equip the protein with new pro-oncogenic functions. Here, we review the mechanisms by which these new functions gained by p53 mutants promote tumorigenesis.

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Section: Introductionmentioning

confidence: 99%

Do Mutations Turn p53 into an Oncogene?

Pitolli

Wang

Mancini

et al. 2019

IJMS

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“…Indeed, the combination of p19Arf and IFNβ is better able to induce melanoma cell death both in vitro and in vivo [110,111]. Strikingly, the mechanism of cell death involves necroptosis with liberation of the classic markers of immunogenic cell death [111]. In a mouse model of melanoma, we have confirmed the induction of an antitumor immune response in vaccine and immunotherapy settings, with critical involvement of NK cells, CD4+ and CD8+ T cells [112].…”

Section: Turning Gene Therapy Into Immunotherapy: Adenovirus-carryingmentioning

confidence: 60%

“…In order to activate the immune response against the tumor, we have added interferon-β (IFNβ) to our therapeutic approach since it is a central player in innate and adaptive immunity [109]. Indeed, the combination of p19Arf and IFNβ is better able to induce melanoma cell death both in vitro and in vivo [110,111]. Strikingly, the mechanism of cell death involves necroptosis with liberation of the classic markers of immunogenic cell death [111].…”

Section: Turning Gene Therapy Into Immunotherapy: Adenovirus-carryingmentioning

confidence: 99%

Gene-based Interventions for Cancer Immunotherapy

Cerqueira¹,

Silva²,

LunaVieira³

et al. 2019

In Vivo and Ex Vivo Gene Therapy for Inherited and Non-Inherited Disorders

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Immunotherapy of cancer has deservedly gained much attention in the past few years and is likely to continue to advance and become a fundamental cancer treatment. While vaccines, chimeric antigen receptor (CAR) T cells and checkpoint blockade have received the lion's share of the attention, an important direct role for gene transfer as an immunotherapy is emerging. For example, oncolytic viruses induce immunogenic cell death, thus liberating both antigens and the signals that are necessary for the activation of antigenpresenting cells, ensuring stimulation of an adaptive response. In another example, transfer of prodrug converting enzymes, such as the herpes simplex virus-thymidine kinase (HSV-tk) gene or the cytosine deaminase gene, has been shown to promote an immune response, thus functioning as immunotherapies. Alternatively, our own work involves the use of nonreplicating viral vectors for the simultaneous delivery of gene combinations that promote both cell death and an immune response. In fact, our gene transfer approach has been applied as a vaccine, immunotherapy or in situ gene therapy, resulting in immunogenic cell death and the induction of a protective immune response. Here, we highlight the development of these approaches both in terms of technical advances and clinical experience.

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“…O uso de IFNβ confere uma resposta de perfil citotóxico (TH1), porém somente sua combinação com p19ARF induz uma resposta de células NK (natural killers), aumenta sobrevida em modelo de vacina profilática e reduz progressão tumoral em modelo de vacina terapêutica [3]. Outro trabalho destacou que o tratamento com p19ARF e IFNβ promove necroptose incluindo sinais de morte imunogênica, revelando assim, em parte, o mecanismo por trás da resposta promovida pela imunoterapia [87,88].…”

Section: Os Vírus Oncolíticosunclassified

Estabelecimento de linhagens celulares de melanoma canino e transdução com vetores adenovirais aprimorados

Silva¹

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pelos ensinamentos, discussões, ideias, direcionamentos e por estar SEMPRE presente. Por ter me recebido em seu grupo, concedido essa incrível oportunidade e por ter confiado em mim. Obrigada por ter me tornado a pesquisadora que sou hoje.Aos alunos e funcionários do ICESP e da Faculdade de Medicina da USP pela incessante colaboração. Á FAPESP pelo financiamento imprescindível para a elaboração e desenvolvimento deste projeto.Aos professores Roger Chammas e Luisa Villa, por serem exemplos de profissionais que eu desejo alcançar.Aos pesquisadores e amigos Daniela, Rodrigo, Marlous, Paulo, Samir, Aline, Igor, Otto, Ruan, Nayara, Nadine, Fernanda e Otavio pelo treinamento, apoio, conselhos, discussões e cafés. Sem vocês este projeto não seria possível. pela colaboração e excelentes discussões e ideias. À minha amiga e sócia Simone Crestoni, pelo incentivo, apoio, por suportar minhas ausências tantas vezes, por ter sido a responsável por abrir as portas para essa jornada e por continuar me fazendo amar a pesquisa. À minha família Marlene, Osmar, Alessandra e Rodrigo por todo amor, carinho, apoio incondicionais, sempre. Ao meu marido Eduardo, pelo amor, compreensão, companheirismo e pela oportunidade maravilhosa de amá-lo. gene TP53 e a avaliação da expressão de genes da via de TP53 induzidos por doxorrubicina e Nutlin-3. RESULTADOS: As quatro linhagens de melanoma canino estabelecidas possuem capacidade tumorigênica e de serem transduzidas pelos vetores adenovirais. Não foram identificadas alterações na sequência do TP53 na região avaliada e a doxorrubicina promoveu aumento da expressão dos transgenes dirigidos pelo promotor PG e a ativação de genes da via de TP53. CONCLUSÕES: A funcionalidade desta plataforma adenoviral aprimorada abre oportunidades para estudos da transferência gênica, incluindo da combinação p19ARF/IFNβ, nas linhagens estabelecidas. Com o sucesso destas análises, teremos um importante modelo experimental a ser utilizado no desenvolvimento de novas terapias para o melanoma. ABSTRACT Silva GRO. Establishment of canine melanoma cell lines and transduction with improved adenoviral vectors [dissertation]. São Paulo: "Faculdade de Medicina, Universidade de São Paulo"; 2019. INTRODUCTION: Melanoma is a cancer of high mortality both in human and veterinary medicine due to the poor response to therapies and the metastatic evolution of the disease. Advances in the field of oncology have shown that agents that target immune system components, as well as molecularly targeted therapies, are very promising for the treatment of melanoma. Our group has developed viral vectors for gene transfer of antitumor factors. The improvement in the adenoviral vector includes the insertion of the RGD tripeptide, which allows a broad transduction tropism, and the use of a p53 responsive promoter to control therapeutic gene expression. Canine melanoma may be considered as an experimental model since it is a spontaneous cancer with biological behavior similar to human melanoma, thus we aim to test our approach, which we call Ad...

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Reestablishment of p53/Arf and interferon-β pathways mediated by a novel adenoviral vector potentiates antiviral response and immunogenic cell death

Cited by 30 publications

References 47 publications

Do Mutations Turn p53 into an Oncogene?

Do Mutations Turn p53 into an Oncogene?

Gene-based Interventions for Cancer Immunotherapy

Estabelecimento de linhagens celulares de melanoma canino e transdução com vetores adenovirais aprimorados

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