Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY This R01 renewal proposal intends to extend the PI's past productivity that includes 35 publications since the year, 2016, including 3 senior-authored manuscripts in Clinical Cancer Research and 2 additional bodies of work that are under review in Neuro-Oncology and Nature. The scientific premise of the PI's renewal application is an extension of continuous NIH/NINDS F32 (Postdoctoral NRSA), NIH/NINDS K99/R00 (Pathway To Independence) and NIH/NINDS R01 support that have collectively focused on the investigation of indoleamine 2,3 dioxygenase 1 (IDO; IDO1) in glioblastoma (GBM). IDO is expressed in >90% of all patient-resected GBM and potently suppresses the anti-GBM immune response. IDO expression is increased by GBM-infiltrating T cells and therefore represents a key mechanism of resistance to immune-based therapies, since targeted approaches that aim to enhance T cell infiltration into GBM, will in-turn, result in a compensatory increase of IDO expression and suppression of the anti-GBM immune response. Importantly, the high intratumoral IDO expression is associated with significantly decreased GBM patient survival and increased immunosuppressive regulatory T cells (CD4+CD25+FoxP3+). Since IDO is canonically characterized as a rate-limiting enzyme that metabolizes the essential amino acid, tryptophan (Trp), into the downstream metabolite, kynurenine (Kyn), the depletion of Trp and/or accumulation of Kyn has been the presumed mechanism of how IDO suppresses the anti-GBM immune response. However, our work has challenged this hypothesis, supported in-part through the creation of 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 increases Tregs and decreases survival independent of tryptophan metabolism. Our collective results indicate that GBM cell IDO represents a complex mechanism of immune resistance that has motivated our development 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 our proposal are therefore to (i) investigate the mechanism responsible for GBM cell IDO enzyme independent immunosuppression 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 improving treatment outcomes of GBM patients that are co-treated with immunotherapy and IDO-PROTACs.
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