Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and is fatal in nearly all cases. Recent success with immune checkpoint blockade (ICB) treatment of patients with specific types of cancer has raised an interest in applying ICB treatment to patients with GBM. Unfortunately, ICB treatment failed to improve the survival of patients with recurrent GBM [Checkmate 143; NCT02017717], as well as in newly-diagnosed GBM patients [Checkmate 498; NCT02617589] among all phase III clinical trials to-date. These negative results led our group to focus on factors expressed by GBM cells that limit the anti-tumor immune response. One such factor is indoleamine 2,3 dioxygenase 1 (IDO) and is expressed in ≥90% of patient-resected GBM. IDO suppresses the immune response through its function as a rate-limiting enzyme that converts the amino acid, tryptophan, into downstream metabolites known as kynurenines. To investigate the effects of tryptophan metabolism on GBM outgrowth, we created IDO-deficient murine GBM cells reconstituted with either (i) empty expression vector, (ii) a vector expressing wild-type IDO, (iii) or a vector expressing enzyme-inactive IDO. When intracranially-engrafted into the syngeneic mouse brain, GBM cell IDO expression increased Tregs and decreased survival independent of tryptophan metabolism. To identify alternative means by which IDO affects GBM outgrowth, we performed a microarray analysis of human GBM cells and discovered that complement factor H (CFH) is significantly increased in GBM cells expressing IDO. When GBM cells were treated with IDO siRNA, CFH expression also decreased. However, IDO regulation of CFH expression was independent of IDO metabolic activity. Our collective results indicate that IDO suppresses the anti-GBM immune response in the absence of tryptophan metabolism and has motivated our development and testing of IDO-proteolysis targeting chimeras (IDO-PROTACs) – compounds that bind to IDO protein and recruit an E3 ubiquitin ligase to facilitate proteasome degradation. IDO-PROTACs enable experiments to address IDO immunosuppressive effects that are enzyme independent. The aims of the proposal are to (i) investigate the mechanism responsible for GBM cell IDO-dependent CFH expression and intratumoral Treg accumulation and (ii) design, create and optimize novel IDO-PROTACs that mediate IDO protein degradation in human GBM cells. Determination of how IDO suppresses the immune response combined with the generation of potent IDO-PROTACs will address knowledge gaps about GBM immunobiology while also developing a new therapeutic approach that can be used to improve treatment outcomes for patients with GBM.
|Effective start/end date||6/1/21 → 6/30/27|
- National Institute of Neurological Disorders and Stroke (2R01NS097851-06)
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