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Doctoral Thesis
DOI
https://doi.org/10.11606/T.42.2021.tde-23032022-112253
Document
Author
Full name
Mariângela de Oliveira Silva
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2021
Supervisor
Committee
Ferreira, Luis Carlos de Souza (President)
Chammas, Roger
Ferreira, Karen Spadari
Santos, Patricia Cruz Bergami
Title in Portuguese
Direcionamento de antígenos para células dendríticas como estratégia imunoterapêutica para o controle de tumores induzidos por HPV.
Keywords in Portuguese
Células dendríticas
HPV
imunoterapia
receptor DEC205
Abstract in Portuguese
As doenças causadas por infecções persistentes por HPV, como o câncer cervical, representam um grave problema de saúde pública no mundo e correspondem a um dos maiores causadores de mortes relacionadas a tumores em mulheres. Neste sentido, a busca por novas abordagens terapêuticas para esse tipo de câncer é uma prioridade. A geração de vacinas anticâncer bem-sucedidas depende da capacidade de induzir respostas imunes contra antígenos tumorais. Neste cenário, o direcionamento de antígenos para as células dendríticas (DCs) representa uma abordagem promissora, capaz de aumentar a eficiência de imunoterapias antitumorais. No presente estudo, utilizamos anticorpos monoclonais (mAbs) capazes de direcionar antígenos para uma população específicas de DCs, as DCs CD8α+ DEC205+. Para isso, anticorpos monoclonais αDEC205 foram fusionados geneticamente à oncoproteína E7 do HPV-16 afim de criar uma vacina capaz de tratar tumores associados ao HPV. A eficácia terapêutica dos mAbs αDEC205-E7 foi avaliada utilizando o modelo de células TC-1 implantadas em três sítios anatômicos distintos (subcutâneo, cavidade oral e intravaginal). O regime de imunização compreendeu duas doses do mAb αDEC205-E7 coadministrado com o adjuvante Poly (I:C). A formulação vacinal produziu efeitos antitumorais robustos nos modelos de implante subcutâneo e ortotópicos, estimulando a regressão rápida do tumor e a sobrevivência a longo prazo. Esses resultados foram relacionados à ativação de células T CD8+ citotóxicas E7-específicas sistêmicas e em tecidos linfoides. Além disso, o tratamento foi capaz de induzir imunidade de longa duração e controlar recidivas tumorais. Em virtude dos resultados promissores obtidos em modelo murino, um mAb específico para DEC205 humano fusionado à proteína E7 (αDEC205-E7 hu) foi também construído e purificado. O mAb αDEC205-E7 hu manteve sua integridade preservada e mostrou-se capaz de ligar-se a DCs derivadas de monócitos (moDCs) e a monócitos humanos. Em ensaios de ativação de DCs in vitro, os mAbs sozinhos não foram capazes de ativar moDCs pelo aumento da expressão das moléculas coestimuladoras CD83 e CD86. Os dados obtidos no presente estudo demostram a importância do direcionamento de antígenos para DCs e a eficiência terapêutica da estratégia proposta. Dessa forma, a utilização do mAb αDEC205-E7 é uma abordagem promissora para o desenvolvimento de imunoterapias contra tumores induzidos por HPV.
Title in English
Targeting of antigens to dendritic cells as an immunotherapeutic strategy to control HPV-induced tumors.
Keywords in English
DEC205 receptor
Dendritic cells
HPV
immunotherapy
Abstract in English
Diseases caused by persistent HPV infections, such as cervical cancer, represent a serious public health problem in the world and are one of the biggest causes of tumor-related deaths in women. In this context, the search for new therapeutic approaches for this type of cancer is a priority. The generation of successful anticancer vaccines depends on the ability to induce immune responses against tumor antigens. In this scenario, antigen targeting to dendritic cells (DCs) represents a promising approach, capable of increasing the efficiency of antitumor immunotherapies. In the present study, we used monoclonal antibodies (mAbs) capable of targeting antigens to a specific population of DCs, the CD8α+ DEC205+ DCs. For this, αDEC205 mAbs were genetically fused to the HPV-16 oncoprotein E7 to create a vaccine capable of treating HPV-associated tumors. The therapeutic efficacy of αDEC205-E7 mAbs was evaluated using the TC-1 cell model implanted in three distinct anatomical sites (subcutaneous, oral cavity and intravaginal). The immunization regimen comprised two doses of the αDEC205-E7 mAbs coadministered with Poly(I:C), as adjuvant. The vaccine formulation produced robust antitumor effects in subcutaneous and orthotopic implant models, stimulating rapid tumor regression and long-term survival. These outcomes were related to the activation of E7-specific cytotoxic CD8+ T cells in systemic and lymphoid tissues. Furthermore, the treatment was able to induce long-lasting immunity and control tumor recurrences. Due to the promising results obtained in a murine model, a mAb specific for human DEC205 fused to E7 protein (αDEC205-E7 hu) was also constructed and purified. The αDEC205-E7hu mAb maintained its integrity preserved and was able to bind monocyte-derived DCs (moDCs) and human monocytes. In in vitro DC activation assays, mAbs alone were not able to activate moDCs by increasing the expression of the costimulatory molecules CD83 and CD86. The data obtained in this study highlighted the importance of targeting antigens to DCs and the therapeutic efficiency of the proposed strategy. Thus, the use of mAb αDEC205-E7 is a promising approach for the development of immunotherapies against HPV-induced tumors.
 
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Release Date
2024-03-22
Publishing Date
2022-12-02
 
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