Glioblastoma multiforme (GBM) is the most common and aggressive form of brain tumor in adults. Median survival for GBM patients is 14.6 months post-diagnosis. A consistent feature of GBM is the intratumoral presence of immunosuppressive regulatory T cells (Treg) that impair patient anti-GBM immune response, coincident with the expression of indoleamine 2,3 dioxygenase 1 (IDO1), a rate-limiting enzyme that converts tryptophan (Trp) to kynurenine (Kyn). Utilizing the orthotopic syngeneic and immunocompetent GL261-C57BL6 engraftment model, I previously demonstrated that shRNA-mediated suppression of IDO1 expression in murine GBM cells significantly decreases intratumoral Treg accumulation coincident with a cytolytic T cell response leading to complete tumor regression. This observation prompted the investigation into pharmacologic inhibition of IDO1 as a means to therapeutically induce anti-GBM immunity. Surprisingly, however, the administration of IDO1 inhibitor had no effect on intratumoral Treg accumulation nor on animal subject survival. A hypothesis that provides an explanation for this paradox, addressing how genetic suppression-, but not pharmacologic inhibition- of IDO1, affects intratumoral Treg accumulation and effector T cell response against GBM, forms the basis of this proposal. Recently, my lab discovered that cells in the tumor microenvironment, but not GBM cells, are responsible for nearly all IDO1-mediated Trp to Kyn catabolism in the GL261-C57BL6 model. This observation, however, raises a question regarding the role of tumor cell-associated IDO1, whose genetic suppression promotes productive T cell response against tumor. A potential answer to this question has emerged in association with our discovery that IDO1 localizes to the nucleus in GBM cells. Based on these observations we propose to: 1) establish IDO1 cell type expression and catabolism in human GBM in situ, 2) investigate IDO1 expression and function in human GBM cells and to 3) determine the function of nuclear IDO1 in GBM cells. The proposed studies aim to investigate clinically-relevant questions and approaches that aim to reverse immunosuppression in glioma, which is the first step to the rational design of effective immunotherapy for patients with incurable brain cancer.
A common feature in glioblastoma multiforme (GBM) is the expression of indoleamine 2,3 dioxgenase 1 (IDO), a rate-limiting enzyme that converts tryptophan (Trp) into kynurenine (Kyn). Using immunocompetent models of GBM, we have determined that, the Trp to Kyn converting function of IDO1 is dispensable for immunosuppression of the anti-GBM immune response in mice. This work intends to validate these findings in human GBM and delineate the non-enzymatic mechanism(s) of IDO1-induced immune evasion in malignant brain tumors.
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