Role of indoleamine 2,3 dioxygenase (IDO) in oncogenesis and immunosuppression of tumors associated with human papillomavirus (HPV)

• Grant number: 17/25544-4
• Support Opportunities: Scholarships in Brazil - Master
• Effective date (Start): January 01, 2018
• Effective date (End): October 31, 2019
• Field of knowledge: Biological Sciences - Microbiology - Applied Microbiology
• Principal Investigator: Ana Carolina Ramos Moreno
• Grantee: Roberta Liberato Pagni
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 15/16505-0 - Indoleamine 2,3 dioxygenase in the biology of papillomaviruses-induced tumors: neoadjuvant effects on the immunetherapy of tumors, AP.JP

Abstract

Human Papillomavirus (HPV) is the etiologic agent of a variety of diseases, such as benign epithelial lesions, genital warts, laryngeal papillomas, and other diseases that are difficult to manage. In recent years, the role of HPV in triggering different types of tumors has been highlighted. It is known that HPV is responsible for more than 99% of cervical tumors, most of the anal tumors and about half of the penile and head and neck cancers. Among the therapeutic failures available in the medical clinic, the tumor refraction is highlighted both to chemotherapies and immunotherapies, mainly due to the immunosuppressive microenvironment generated by the tumors. In this context, studies show that the indoleamine 2,3-dioxygenase (IDO) enzyme is an important mediator of tumor evasion to the immune response. Some papers show the importance of the presence of IDO1 in HPV+ tissues and tumors. However, the role of IDO in this landscape is still unknown. The objective of the present project will be to evaluate the cellular mechanisms mediated by IDO in the genesis, maintenance and progression of HPV+ tumors, in addition to evaluating the impact of IDO on the antitumor properties conferred by an HPV-16+ tumor vaccine, developed in the Laboratory of Development of Vaccines (LDV) of ICB-USP. In the first phase, the differences in cell populations that compose the microenvironments of the blood, spleen, intestine and tumor of wild-type C57BL/6 animals versus IDO-deficient animals (IDO-KO) at different stages of tumor growth will be addressed. The tumor model that will be used is based on TC-1 cells, which express the HPV-16 E6 and E7 oncoproteins. In addition, TC-1 cells silenced in IDO will also be used by the CRISPR/Cas9 technique. In the second phase the research will aim to characterize the cellular mechanisms involved in the antitumor effect of the LDV therapeutic vaccine (gDE7) associated with IDO inhibitors. New analyzes of the microenvironment of the blood, spleen, intestine and tumor will be performed in the search for effector and specific immune responses. Once the importance of IDO in HPV-associated tumors has been established, therapeutic alternatives may be designed more specifically and efficiently. (AU)

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)

MORENO, ANA C. R.; PORCHIA, BRUNA F. M. M.; PAGNI, ROBERTA L.; SOUZA, PATRICIA DA CRUZ; PEGORARO, RAFAEL; RODRIGUES, KARINE B.; BARROS, TACITA B.; DE MELO MORAES APS, LUANA R.; DE ARAUJO, ELISEU F.; CALICH, VERA L. G.; et al. The Combined Use of Melatonin and an Indoleamine 2,3-Dioxygenase-1 Inhibitor Enhances Vaccine-Induced Protective Cellular Immunity to HPV16-Associated Tumors. FRONTIERS IN IMMUNOLOGY, v. 9, AUG 22 2018. (16/23189-0, 11/20917-0, 16/00708-1, 15/16505-0, 13/15360-2, 17/25544-4)