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

Author(s)

Manrique-Rincon, Andrea J. ^{[1, 2]} ; Ruas, Luciana P. ^[1] ; Fogagnolo, Carolinne T. ^{[1, 3]} ; Brenneman, Randall J. ^[4] ; Berezhnoy, Alexey ^[4] ; Castelucci, Bianca ^{[1, 5]} ; Consonni, Silvio R. ^[5] ; Gilboa, Eli ^[4] ; Bajgelman, Marcio C. ^{[6, 1, 2]}

Affiliation

^[1] Brazilian Ctr Res Energy & Mat CNPEM, Brazilian Biosci Natl Lab LNBio, BR-13083100 Campinas - Brazil

^[2] Univ Campinas UNICAMP, Sch Med, BR-13083887 Campinas - Brazil

^[3] Univ Sao Paulo, Ribeirao Preto Med Sch, Biomed Sci, BR-14049900 Ribeirao Preto - Brazil

^[4] Univ Miami, Dodson Interdisciplinary Immunotherapy Inst & Syl, Miller Sch Med, Dept Microbiol & Immunol, Miami, FL 33136 - USA

^[5] Univ Campinas UNICAMP, Inst Biol, BR-13083862 Campinas - Brazil

^[6] Univ Estadual Campinas, Fac Pharmaceut Sci, BR-13083871 Campinas, SP - Brazil

• Document type: Journal article
• Source: MOLECULAR THERAPY-NUCLEIC ACIDS; v. 25, p. 143-151, SEP 3 2021.
• Web of Science Citations: 0

Abstract

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. (AU)

• FAPESP's process: 19/04458-8 - Development of biological nanoparticles to boost antitumor immunity
• Grantee: Marcio Chaim Bajgelman
• Support Opportunities: Regular Research Grants
• FAPESP's process: 12/13132-0 - Exploration of molecular targets to inhibit regulatory T cells and potentiate antitumoral immunity
• Grantee: Marcio Chaim Bajgelman
• Support Opportunities: Regular Research Grants
• 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)