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Exploration of molecular targets to inhibit regulatory T cells and potentiate antitumoral immunity

Abstract

Regulatory T cells (Treg) have the unique property of suppressing the proliferation of effector T cells, promoting immunological tolerance. Clinical samples isolated from patients revealed that the infiltrate of Tregs in the tumoral site correlates with the progression of cancer. Literature data suggest 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 isn't specific and also causes the elimination of other CD25 positive cell populations, such as CD4 effector T cells that could contribute to antitumor immunity.In this project, we plan to explore molecular mechanisms to inhibit specific targets associated to the establishment and maintenance of the suppressor phenotype of regulatory T cells. We are going to generate RNA interference molecules (RNAi) to silence the expression of target genes with high specificity and high efficiency. These RNAi molecules will be delivered in vitro, using retroviral vectors, to verify inhibition of suppressive phenotype of Tregs. Additionally, we also are going to develop a non-viral platform based on chimerical RNA aptamers, that can be used to deliver inhibitory molecules in vivo through cell surface receptors on regulatory T cells. The RNA aptamers have low immunogenicity, high selectivity and allow in vivo application. We expect that the inactivation of the molecular targets of this study leads to the functional blocking, enhancing the antitumor immune response in animals challenged.In this way, mechanisms and platforms explored in this project can contribute to the development of potential strategies to enhance antitumor therapies. (AU)

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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)
CONSONNI, SILVIO R.; DE CARVALHO, ANNA C. P. V.; MAURO, ARTUR B.; FRANCHINI, KLEBER G.; BAJGELMAN, MARCIO C. Lentiviral transduction of neonatal rat ventricular myocytes preserves ultrastructural features of genetically modified cells. VIROLOGY, v. 562, p. 190-196, OCT 2021. Web of Science Citations: 0.
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.; 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.

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