A therapeutic DNA vaccine and gemcitabine act synergistically to eradicate HPV-associated tumors in a preclinical model

Author(s):Show less -

Ramos da Silva, Jamile ^[1] ; Ramos Moreno, Ana Carolina ^[1] ; Silva Sales, Natiely ^[1] ; de Oliveira Silva, Mariangela ^[1] ; Aps, Luana R. M. M. ^[1] ; Porchia, Bruna F. M. M. ^{[2, 1]} ; Bitencourt Rodrigues, Karine ^[1] ; Cestari Moreno, Natalia ^{[3, 4]} ; Venceslau-Carvalho, Alexia Adrianne ^[1] ; Menck, Carlos Frederico M. ^[3] ; de Oliveira Diniz, Mariana ^{[1, 5]} ; de Souza Ferreira, Luis Carlos ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Microbiol, Vaccine Dev Lab, Ave Prof Lineu Prestes 1374, BR-05508000 Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Lab Tumor Immunol, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Inst Biomed Sci, Dept Microbiol, DNA Repair Lab, Sao Paulo - Brazil

^[4] Univ Sao Paulo, Inst Chem, Dept Biochem, Mitochondrial Genet Lab, Sao Paulo - Brazil

^[5] UCL, Div Infect & Immun, 5 Univ St, London - England

• Document type: Journal article
• Source: ONCOIMMUNOLOGY; v. 10, n. 1 JAN 1 2021.
• Web of Science Citations: 0

Abstract

Although active immunotherapies are effective strategies to induce activation of CD8(+) T cells, advanced stage tumors require further improvements for efficient control. Concerning the burden of cancer-related to Human papillomavirus (HPV), particularly the high incidence and mortality of cervical cancer, our group developed an approach based on a DNA vaccine targeting the HPV-16 E7 oncoprotein (pgDE7h). This immunotherapy is capable of inducing an antitumour CD8(+) T cell response but show only partial control of tumors in more advanced growth stages. Here, we combined a chemotherapeutic agent (gemcitabine- Gem) with pgDE7h to overcome immunosuppression and improve antitumour responses in a preclinical mouse tumor model. Our results demonstrated that administration of Gem had synergistic antitumor effects when combined with pgDE7h leading to eradication of both early-stages and established tumors. Overall, the antiproliferative effects of Gem observed in vitro and in vivo provided an optimal window for immunotherapy. In addition, the enhanced antitumour responses induced by the combined therapeutic regimen included enhanced frequencies of antigen-presenting cells (APCs), E7-specific IFN-gamma-producing CD8(+) T cells, and cytotoxic CD8(+) T cells and, concomitantly, less pronounced accumulation of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). These findings demonstrated that the combination of Gem and an active immunotherapy strategy show increased effectiveness, leading to a reduced need for multiple drug doses and, therefore, decreased deleterious side effects avoiding resistance and tumor relapses. Altogether, our results provide evidence for a new and feasible chemoimmunotherapeutic strategy that supports future clinical translation. (AU)

• FAPESP's process: 11/51218-0 - Immunotherapy against human papillomavirus (HPV) induced tumors
• Grantee: Mariana de Oliveira Diniz
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 16/14344-1 - Control tumors induced by HPV -based immunotherapy in combination monoclonal antibodies blocking immunosuppressive pathways a therapeutic vaccine capable of activating CD8 + cytotoxic T lymphocytes
• Grantee: Natiely Silva Sales
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 16/00708-1 - Indoleamine 2,3 dioxygenase in the biology of papillomaviruses-induced tumors: neoadjuvant effects on the immunetherapy of tumors
• Grantee: Ana Carolina Ramos Moreno
• Support Opportunities: Scholarships in Brazil - Young Researchers
• FAPESP's process: 15/16505-0 - Indoleamine 2,3 dioxygenase in the biology of papillomaviruses-induced tumors: neoadjuvant effects on the immunetherapy of tumors
• Grantee: Ana Carolina Ramos Moreno
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 18/26555-2 - Study of role of DNA polymerase eta in cellular responses and carcinogenesis induced by ultraviolet light A
• Grantee: Natália Cestari Moreno
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 16/11397-7 - Targeting antigens to dendritic cells as an immunotherapeutic strategy to control HPV-induced tumors
• Grantee: Mariângela de Oliveira Silva
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 17/21358-1 - Human papillomavirus (HPV)-associated neoplasia: a new therapeutic approach based on active immunotherapy through targeted stimulation of dendritic cells
• Grantee: Bruna Felício Milazzotto Maldonado Porchia Ribeiro
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 16/11594-7 - Self-amplifying RNA as immunotherapeutic strategy for the control of tumors induced by HPV-16
• Grantee: Jamile Ramos da Silva
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 14/11073-1 - Co-expression of IL-10 receptor as a strategy to enhance the effects of a DNA vaccine focused on the control of tumors induced by HPV-16
• Grantee: Jamile Ramos da Silva
• Support Opportunities: Scholarships in Brazil - Master