Inactivation of regulatory T cells by transcriptional gene silencing of Foxp3 to potentiate antitumor immunity

Author(s)

Andrea Johanna Manrique Rincón

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas
• Defense date: 2017-12-20

Examining board members

Marcio Chaim Bajgelman; Margareth Castro Ozelo; José Alexandre Marzagão Barbuto; Raquel Chacon Ruiz Martinez; Welbert de Oliveira Pereira

• Advisor: Marcio Chaim Bajgelman

Abstract

Immunotherapy for cancer has developed remarkably in the last decade, however, despite these efforts, there are still mechanisms used by tumor cells to evade the immune system. Tumor biopsies reveal that regulatory T-cell infiltrates (Treg) at the tumor site correlate with cancer progression, because of their ability to antagonize the action of effector lymphocytes. In this way, the specific elimination of Treg may act in synergy with other antitumor therapies. There are strategies for the inhibition of Treg, however, due to the lack of selectivity, these approaches also eliminate other effector lymphocytes, thus acting antagonistically to antitumor immunity. The transcription factor FOXP3, present almost exclusively in Treg, plays a central role associated with the maintenance of the immunosuppressive phenotype in these cells. Due to the fact that FOXP3 is inaccessible to antibodies, in this work we have developed a new immunotherapy strategy to inhibit Treg cells based on the delivery of RNAi molecules for the transcriptional gene silence (TGS) of Foxp3 and, consequently, inhibiting the immunosuppressive phenotype. We chose as target some CpG sites in the promoter and also in the enhancer Treg-specific demethylated region (TSDR) region. In contrast to post-transcriptional gene silencing that aims to inhibit the messenger RNA, which is constitutively expressed in the cell, the TGS system targets the cellular genome, and a single molecule is enough to block the gene expression of Foxp3. We performed the delivery of the TGS-RNAi molecules through a platform of viral vectors that enabled a proof of concept, later improved for a second platform based on chimeric aptamers that may increase the potential for developing future clinical applications. In addition, we show in this work, results of a study with antitumor vaccines for T cells costimulation that may act in synergy with the depletion of regulatory T cells strategies, to enhance the antitumor immune response (AU)

• FAPESP's process: 13/02041-6 - Development of a FoxP3 transcriptional silencing strategy to inactivate regulatory T cells and potentiate antitumor immunity
• Grantee: Andrea Johanna Manrique Rincón
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)