Aptamer-mediated transcriptional gene silencing of Foxp3 inhibits regulatory T cells and potentiates antitumor response

The inhibition of immunosuppressive mechanisms may switch the balance between tolerance and surveillance, leading to an increase in antitumor activity. Regulatory T cells play an important role in the control of immunosuppression, exhibiting the unique property of inhibiting T cell proliferation. These cells migrate to tumor sites or may be generated at the tumor site itself from the conversion of lymphocytes exposed to tumor microenvironment signaling. Because of the high similarity between regulatory T cells and other lymphocytes, the available approaches to inhibit this population are nonspecific and may antagonize antitumor response. In this work we explore a new strategy for inhibition of regulatory T cells based on the use of a chimeric aptamer targeting a marker of immune activation harboring a small antisense RNA molecule for transcriptional gene silencing of Foxp3, which is essential for the control of the immunosuppressive phenotype. The silencing of Foxp3 inhibits the immunosuppressive phenotype of regulatory T cells and potentiates the effect of the GVAX antitumor vaccine in immunocompetent animals challenged with syngeneic tumors. This novel approach highlights an alternative method to antagonize regulatory T cell function to augment antitumor immune responses. [Display omitted] Here we have generated a chimeric aptamer that binds to 4-1BB receptor that is constitutively expressed in Tregs to vehiculate a transcriptional RNAi silencing molecule targeting FoxP3. Silencing FoxP3 in Tregs may inhibit immunosuppressive phenotype and potentiate antitumor response.