Development of a FoxP3 transcriptional silencing strategy to inactivate regulatory T cells and potentiate antitumor immunity

• 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 researcher: Marcio Chaim Bajgelman
• Grantee: Andrea Johanna Manrique Rincón
• Home Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovações (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)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MANRIQUE-RINCON, ANDREA J.; RUAS, LUCIANA P.; FOGAGNOLO, CAROLINNE T.; BRENNEMAN, RANDALL J.; BEREZHNOY, ALEXEY; CASTELUCCI, BIANCA; CONSONNI, SILVIO R.; GILBOA, ELI; BAJGELMAN, MARCIO C. Aptamer-mediated transcriptional gene silencing of Foxp3 inhibits regulatory T cells and potentiates antitumor response. MOLECULAR THERAPY-NUCLEIC ACIDS, v. 25, p. 143-151, SEP 3 2021. Web of Science Citations: 0.

MANRIQUE-RINCON, ANDREA J.; DE CARVALHO, ANNA C.; EUGENIA RIBEIRO DE CAMARGO, M.; FRANCHINI, KLEBER G.; BAJGELMAN, MARCIO C. Development of a flow cytometry assay which allows to evaluate the efficiency of immunomodulatory vaccines to enhance T cell-mediated antitumor response. Journal of Biotechnology, v. 284, p. 11-16, OCT 20 2018. Web of Science Citations: 1.

MANRIQUE-RINCON, ANDREA J.; BERALDO, CAMILA M.; TOSCARO, JESSICA M.; BAJGELMAN, MARCIO C. Exploring Synergy in Combinations of Tumor-Derived Vaccines That Harbor 4-1BBL, OX40L, and GM-CSF. FRONTIERS IN IMMUNOLOGY, v. 8, SEP 19 2017. Web of Science Citations: 1.