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Targeting of antigens to dendritic cells as an immunotherapeutic strategy to control HPV-induced tumors.

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Mariângela de Oliveira Silva
Total Authors: 1
Document type: Doctoral Thesis
Press: São Paulo.
Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
Defense date:
Examining board members:
Luis Carlos de Souza Ferreira; Roger Chammas; Karen Spadari Ferreira; Patricia Cruz Bergami Santos
Advisor: Luis Carlos de Souza Ferreira; Silvia Beatriz Boscardin

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 CD8&#945+ DEC205+ DCs. For this, &#945DEC205 mAbs were genetically fused to the HPV-16 oncoprotein E7 to create a vaccine capable of treating HPV-associated tumors. The therapeutic efficacy of &#945DEC205-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 &#945DEC205-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 (&#945DEC205-E7 hu) was also constructed and purified. The &#945DEC205-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 &#945DEC205-E7 is a promising approach for the development of immunotherapies against HPV-induced tumors. (AU)

FAPESP's process: 18/07629-5 - Targeting antigens to dendritic cells as an immunotherapeutic strategy to control HPV-induced tumors
Grantee:Mariângela de Oliveira Silva
Support Opportunities: Scholarships in Brazil - Doctorate (Direct)