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Indoleamine 2,3 dioxygenase in the biology of papillomaviruses-induced tumors: neoadjuvant effects on the immunetherapy of tumors

Grant number: 15/16505-0
Support type:Research Grants - Young Investigators Grants
Duration: March 01, 2016 - February 29, 2020
Field of knowledge:Biological Sciences - Immunology - Applied Immunology
Principal Investigator:Ana Carolina Ramos Moreno
Grantee:Ana Carolina Ramos Moreno
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Assoc. researchers:Ana Paula Lepique ; Bruna Felício Milazzotto Maldonado Porchia Ribeiro ; Carina Buzzo de Lima ; Eliseu Frank de Araujo ; Luis Carlos de Souza Ferreira ; Luisa Lina Villa ; Vera Lucia Garcia Calich
Associated scholarship(s):17/25544-4 - Role of indoleamine 2,3 dioxygenase (IDO) in oncogenesis and immunosuppression of tumors associated with human papillomavirus (HPV), BP.MS
16/00708-1 - Indoleamine 2,3 dioxygenase in the biology of papillomaviruses-induced tumors: neoadjuvant effects on the immunetherapy of tumors, BP.JP


In the last twelve years, solid evidence showed that the enzyme Indoleamine 2,3 dioxygenase-1 (IDO) is an important mediator of immune tolerance. While the similarities between IDO regulatory mechanisms and the molecular signature associated with cervical cancer and other tumors induced by human papillomavirus (HPV), the active role of IDO in these tumors has not been studied. Here, we will study two important fields that can support the success of an antitumor therapeutic approach. In the first phase, we will evaluate the link of the molecular mechanisms related to IDO and the profile of the immune response regarding HPV-associated tumors. Therefore, we will evaluate the cellular and molecular parameters using different in vitro and in vivo experimental models, as well as human biopsies. Moreover, knockout mice Ido (-/-), aryl hydrocarbon receptor (AHR) Ahr (-/-) and IL-6 (-/-) will be used for a robust assessment of the role of IDO in this tumor model. Once the parameters were established, the second stage of our research aims to develop a therapeutic approach based on the consortium of an IDO inhibitor (1-methyl-tryptophan) and an anti-oxidant (melatonin) with a specific anti-tumor vaccine formulation against HPV-induced tumors. We will evaluate the phenotype and function of specific T CD8+ cells, and other cell parameters, to establish the relevance of these events in a protective immunity activation achieved by the combination of the neoadjuvant therapy and antitumor vaccines. This research has innovative features, which could impact on the translation of basic science into clinical interventions, and promotes the nucleation of a new research frontline in the University of São Paulo. (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)
SILVA, JAMILE R.; SALES, NATIELY S.; SILVA, MARIANGELA O.; APS, LUANA R. M. M.; MORENO, ANA C. R.; RODRIGUES, ELAINE G.; FERREIRA, LUIS C. S.; DINIZ, MARIANA O. Expression of a soluble IL-10 receptor enhances the therapeutic effects of a papillomavirus-associated antitumor vaccine in a murine model. CANCER IMMUNOLOGY IMMUNOTHERAPY, v. 68, n. 5, p. 753-763, MAY 2019. Web of Science Citations: 1.
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.; DE SOUZA FERREIRA, LUIS C. 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. Web of Science Citations: 0.
PORCHIA, BRUNA F. M. M.; MORENO, ANA CAROLINA R.; RAMOS, RODRIGO N.; DINIZ, MARIANA O.; DE ANDRADE, LAIS HELENA T. M.; ROSA, DANIELA S.; BARBUTO, JOSE ALEXANDRE M.; BOSCARDIN, SILVIA B.; FERREIRA, LUIS CARLOS S. Herpes Simplex Virus Glycoprotein D Targets a Specific Dendritic Cell Subset and Improves the Performance of Vaccines to Human Papillomavirus-Associated Tumors. MOLECULAR CANCER THERAPEUTICS, v. 16, n. 9, p. 1922-1933, SEP 1 2017. Web of Science Citations: 3.

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