Exploration of molecular targets to inhibit regulatory T cells and potentiate anti...
| Grant number: | 13/02041-6 |
| Support type: | Scholarships in Brazil - Doctorate (Direct) |
| Effective date (Start): | August 01, 2013 |
| Effective date (End): | December 31, 2017 |
| Field of knowledge: | Biological Sciences - Genetics - Human and Medical Genetics |
| Principal Investigator: | Marcio Chaim Bajgelman |
| Grantee: | Andrea Johanna Manrique Rincón |
| Home Institution: | Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia, Inovações e Comunicações (Brasil). Campinas , SP, Brazil |
Abstract Clinical samples isolated from patients revealed that the infiltrate of regulatory T cells (Tregs) in the tumor site correlates with the progression of cancer. Data from literature suggests that elimination of Treg cells may act in synergy with other anticancer therapies. Among the most popular strategies, regulatory T cells can be inactivated by depletion, using antibodies or toxins directed to IL-2 receptor (CD25), however, the depletion mechanism mediated by CD25 receptor is not specific and causes the elimination of other CD25 positive cell populations, such as CD4 effector T cells that could contribute to antitumor immunity. Like CD25, most of the cell surface receptors constitutively expressed on Tregs are also expressed on activated T cells and cannot be used to specifically target T reg inhibition. On the other hand, several studies have shown that FoxP3 transcription factor plays an important role associated with the maintenance of regulatory T cell phenotype and could be a good target to inactivate regulatory T cells. Since FoxP3 is inaccessible to antibodies, we aim to develop a new strategy targeting regulatory T cells, based on delivery of specific and efficient molecules of transcriptional gene silencing (TGS) RNAi molecules to inhibit the expression of the FOXP3. We are going to develop enhanced recombinant viral vectors to deliver TGS-RNAi to target cells, to assure both a transduction and transcriptional specificity. These vectors will be used as a proof of concept that TGS-RNAi inactivates suppressive phenotype of Treg. Moreover, we also introduce a new strategy to inhibit FoxP3 expression, using siRNA-aptamer conjugates to deliver TGS-RNAi. Since aptamers are low immunogenic, this tool can be used to deliver TGS-RNAi in vivo, to inhibit FoxP3, and inactivate suppressive phenotype of Treg and boosting immune response against tumor cells. The success of these strategies may allow development of new approaches to cancer immunotherapy. (AU) | |
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