The role of IDO enzyme on the expression of CTLA-4 immune checkpoint on the T lymphocyte cells in mammary câncer

• Ano de defesa: 2025
• Autor(a) principal: Sorkhabi, Parviz Azimnasab
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: eng
• Instituição de defesa: Biblioteca Digitais de Teses e Dissertações da USP
• Palavras-chave em Português: Cancer; Câncer; Células T; Células T reguladoras(Treg); Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4); Indoleamina 2,3-dioxigenase (IDO); Indoleamine 2,3-dioxygenase (IDO); Proteína de ligação à sequência rica em AT (SATB1); Regulatory T (Treg) cells; Special AT-rich Sequence-Binding Protein 1 (Satb1); T cell
• Link de acesso: https://www.teses.usp.br/teses/disponiveis/10/10132/tde-11082025-153928/

In this dissertation, we aim to gain a deeper understanding the function of the of the indoleamine 2,3-dioxygenase (IDO) enzyme in the tumor microenvironment, particularly its impact on T cell function. We used a combination of in vitro and in vivo approaches, including different administration strategies, tumor models, and survival analyses, to evaluate the role of IDO in tumor progression. While our in vitro experiments revealed a significant influence of IDO on T cells, especially regulatory T cells (Tregs), these effects were not observed in our in vivo models, where IDO blockade alone failed to suppress tumor growth. This discrepancy led us to investigate why IDO inhibition alone may not be sufficient for tumor control. To address this, we applied bioinformatic analysis using publicly available datasets from human breast cancer samples to explore broader mechanisms. Notably, we observed a marked reduction in SATB1 expression in Treg cells following IDO blockade in vitro. Given SATB1’s role as a key chromatin organizer and regulator of Treg cell identity, we further explored potential interactions between IDO and SATB1 using in silico approaches. Overall, this study integrates both experimental and computational approaches to investigate the intricate interplay between metabolic and epigenetic mechanisms regulating T cell function in the tumor microenvironment. Our findings suggest that the immunosuppressive effects previously attributed solely to the IDO enzyme may also involve other tryptophan-catabolizing enzymes, such as IL4i1. These enzymes contribute to the depletion of tryptophan and the accumulation of immunoregulatory metabolites that suppress antitumor immunity, particularly through effects on T cells, including regulatory T cells (Tregs). Therefore, targeting IDO alone may be insufficient to achieve meaningful therapeutic outcomes. A combinatorial strategy that simultaneously inhibits multiple tryptophan-metabolizing enzymes may be necessary to more effectively disrupt the immunosuppressive metabolic environment and reduce tumor burden.