Date of Award

Fall 9-23-2025

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Neuroscience

First Advisor

Derek Wainwright

Abstract

Glioblastoma (GBM) is the most common and most aggressive form of adult cancer in the central nervous system, with GBM accounting for the majority of all malignant brain tumors. GBM is currently considered to be an incurable form of cancer, with over 14,000 patients diagnosed in the United States last year. Given the success of immunotherapy for treating other types of cancer, our group has investigated the possibility of therapeutically neutralizing immunosuppressive indoleamine 2,3 dioxygenase 1 (IDO1) in patients with GBM. Canonically, IDO1 is an immunosuppressive cytoplasmic enzyme that catalyzes the first step in metabolizing L-tryptophan into L-kynurenine (ie. ↓L-Trp→↑L-Kyn). In vitro, GBM cell IDO1 expression leads to L-Trp depletion and/or L-Kyn accumulation, leading to the functional inhibition of co-cultured T cells. Additionally, higher patient resected GBM IDO1 expression levels are significantly correlated with worse GBM patient survival outcomes. Surprisingly, however, pharmacological IDO1 enzyme inhibitor (IDO1i) treatment (ie. ↑L-Trp→↓L-Kyn) of immunocompetent mice with intracranial GBM does not improve their overall survival. This preclinical finding is consistent with 5 different phase 3 clinical trials that determined IDO1 enzyme inhibitor treatment fails to improve survival in human patients with cancer. This raises critical questions about the mechanism(s) of IDO1 enzyme inhibitor treatment and how it interacts with the tumor microenvironment during treatment. We previously investigated the effects of IDO1 enzyme inhibitor on GBM cell IDO1 activity in whole cell lysate (WCL), exosomes, and vesicle free media (VFM) fractions. The results show a novel effect whereby the treatment with an IDO1 enzyme inhibitor significantly enriches IDO1 protein outside of the cell and in the VFM fraction. This preliminary observation is striking since it was recently reported that extracellularly localized IDO1 mediates an immunosuppressive effect. My thesis work aims to investigate the mechanism by which IDO1 enzyme inhibitor treatment confers a gain-of-function to IDO1 that causes its extracellular enrichment, and in-turn, mediates a novel immunosuppressive function.

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