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Role of indoleamine 2,3-dioxigenase (IDO) in the oncogenesis and immunosuppression of tumors associated with Human Papillomavirus (HPV)

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Author(s):
Roberta Liberato Pagni
Total Authors: 1
Document type: Master's Dissertation
Press: São Paulo.
Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
Defense date:
Examining board members:
Ana Carolina Ramos Moreno; Humberto Dellê; Paulo Lee Ho; Enrique Mario Boccardo Pierulivo
Advisor: Ana Carolina Ramos Moreno
Abstract

Immunotherapy has become an important ally in the fight against different types of cancer. However, the metabolic plasticity of the tumor environment often influences the effectiveness of therapeutic procedures. In this scenario, immunometabolic adjuvants arise as an alternative for the development of new therapies against cancer. Solid evidence shows that the enzyme indoleamine 2,3-dioxigenase-1 (IDO1) is an important mediator of tumor evasion to the immune response. Although the similarity between the mechanisms of regulation of IDO1 and the molecular signature associated with cervical cancer and other types of tumors associated with human papillomavirus (HPV) is remarkable, the active role of IDO1 in these tumors is still poorly studied. In the present work, we set out to study a new therapeutic approach for the treatment of tumors associated with HPV. The proposed immunotherapy has two treatment fronts: 1-methyl-tryptophan (1-MT) and the therapeutic vaccine gDE7, specific for HPV-16. The IDO inhibitors (being the D-1MT enantiomer and racemic mixture DL-1MT) were chosen to compose based on non-clinical and clinical data as immunometabolic adjuvants to antitumor therapies. The gDE7 vaccine, in turn, showed excellent therapeutic effects in experimental conditions based on mice transplanted with TC-1 cells, a murine tumor line that encodes the HPV-16 E6 and E7 oncoproteins. The main aspects identified in this study were: 1) IDO1 is present and is enzymatically active in TC-1 tumor cells, which allows the use of this animal model in the search for new therapeutic alternatives for tumors associated with HPV; 2) There is an increase in the expression of IDO1 in intratumor leukocytes in the course of tumor growth, which favors the installation of an immunosuppressive microenvironment, and elects this enzyme as a therapeutic target in a cancer model associated with HPV-16; 3) The absence of expression of IDO1 in leukocytes and stromal cells, but not in tumor cells, increases the efficiency of active immunotherapy, particularly of the gDE7 vaccine; 4) The use of IDO1 inhibitors, such as 1MT, in combination with the gDE7 vaccine, favors the control of the tumor mass, but it is not enough to induce the total regression of the tumors; 5) The absence of IDO1 has a direct impact on decreasing the expression of the AhR receptor in dendritic cells, which can impact the modulation of the immune cell phenotype, with consequent control of the growth of the tumor mass; 6) The absence of interleukin-6 (IL-6) expression in leukocytes and stromal cells, but not in tumor cells, slows the growth of TC-1 cell tumors; 7) The association of 1-MT with the gDE7 vaccine, when administered mainly to animals deficient in IL-6, favors the control of the tumor mass, which suggests that IL-6 could also be a therapeutic target and indicates the need for different therapeutic combinations for successful treatment. In view of our experimental findings, the unprecedented combination of IDO inhibitors with the gDE7 vaccine, especially in the absence of IL-6, represents a promising new therapeutic alternative to improve the effectiveness of treatments for tumors associated with HPV. (AU)

FAPESP's process: 17/25544-4 - Role of indoleamine 2,3 dioxygenase (IDO) in oncogenesis and immunosuppression of tumors associated with human papillomavirus (HPV)
Grantee:Roberta Liberato Pagni
Support Opportunities: Scholarships in Brazil - Master