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

Abstract

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)