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


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)

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Scientific publications (6)
(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)
RAMOS DA SILVA, JAMILE; RAMOS MORENO, ANA CAROLINA; SILVA SALES, NATIELY; DE OLIVEIRA SILVA, MARIANGELA; APS, LUANA R. M. M.; PORCHIA, BRUNA F. M. M.; BITENCOURT RODRIGUES, KARINE; CESTARI MORENO, NATALIA; VENCESLAU-CARVALHO, ALEXIA ADRIANNE; MENCK, CARLOS FREDERICO M.; et al. A therapeutic DNA vaccine and gemcitabine act synergistically to eradicate HPV-associated tumors in a preclinical model. ONCOIMMUNOLOGY, v. 10, n. 1, . (11/51218-0, 16/14344-1, 16/00708-1, 15/16505-0, 18/26555-2, 16/11397-7, 17/21358-1, 16/11594-7, 14/11073-1)
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, . (16/00708-1, 16/14344-1, 15/16505-0, 16/11397-7, 13/15360-2, 11/51218-0, 14/11073-1)
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, . (09/54599-5, 16/00708-1, 11/20917-0, 15/16505-0, 11/08905-7, 11/51218-0, 14/15061-8)
SILVA, MARIANGELA O.; ALMEIDA, BIANCA S.; SALES, NATIELY S.; DINIZ, MARIANA O.; APS, LUANA R. M. M.; RODRIGUES, KARINE B.; SILVA, JAMILE R.; MORENO, ANA C. R.; PORCHIA, BRUNA F. M. M.; SULCZEWSKI, FERNANDO B.; et al. Antigen Delivery to DEC205(+) Dendritic Cells Induces Immunological Memory and Protective Therapeutic Effects against HPV-Associated Tumors at Different Anatomical Sites. International Journal of Biological Sciences, v. 17, n. 11, p. 2944-2956, . (18/26515-0, 18/07629-5, 15/16505-0, 16/00708-1, 18/07142-9)
MILAZZOTTO MALDONADO PORCHIA, BRUNA FELICIO; DE MELO MORAES APS, LUANA RAPOSO; RAMOS MORENO, ANA CAROLINA; DA SILVA, JAMILE RAMOS; SILVA, MARIANGELA DE OLIVEIRA; SALES, NATIELY SILVA; DOS SANTOS ALVES, RUBENS PRINCE; REILY ROCHA, CLARISSA RIBEIRO; SILVA, MATHEUS MOLINA; RODRIGUES, KARINE BITENCOURT; et al. Active immunization combined with cisplatin confers enhanced therapeutic protection and prevents relapses of HPV-induced tumors at different anatomical sites. International Journal of Biological Sciences, v. 18, n. 1, p. 15-29, . (11/13805-1, 20/13640-1, 11/20917-0, 17/21358-1, 13/15360-2, 15/16505-0, 18/08502-9)
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, . (16/23189-0, 11/20917-0, 16/00708-1, 15/16505-0, 13/15360-2, 17/25544-4)

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