Effective immunotherapy of glioblastoma (GBM) remains to be a significant challenge due to the strong immunosuppression induced by the tumor. Thus, inhibiting glioblastoma-induced immunosuppression is a critical strategy for the successful treatment of this deadly disease. Recent work from our laboratory has identified indoleamine 2,3 dioxygenase (IDO) as a strong candidate that is critically involved in regulating glioma-induced immunosuppression. IDO is an inducible enzyme that converts the essential amino acid, tryptophan, to the metabolite, kynurenine (Kyn.). Clinically-relevant, the upregulation of IDO in glioma is a strong prognostic factor for predicting decreased patient survival, when compared to downregulated IDO- expressing glioma specimens (p<0.005). Furthermore, our preliminary data show that IDO-competent brain tumors are infiltrated by significantly more regulatory T cells (Tregs;CD4+FoxP3+) with higher GITR expression, when compared to IDO-deficient brain tumors. Given the potent immunosuppressive function of Tregs, combined with GITR in mediating Treg function, we hypothesized that some aspect of IDO's enzymatic activity directly affects Treg homeostasis. Supporting this rationale is the recent in vitro finding that interaction of Kyn. with the aryl hydrocarbon receptor (Ahr) in CD4+ T cells leads to the expression of FoxP3. Based on these collective observations, we propose the central hypothesis that: glioma-derived IDO increases Kyn. levels resulting in Ahr-dependent Treg expansion and GITR-mediated Treg stability and/or recruitment. To investigate this hypothesis, we propose: (1) to confirm the relevance of IDO in a novel transgenic model of glioma, as well as (2) to study the regulation of IDO-mediated Kyn. production-, (3) to determine the impact of the Kyn.-Ahr interaction on Treg expansion and immunosuppression-, as well as (4) to investigate the role of GITR in intratumoral Tregs- using orthotopic mouse models of glioma.
The specific aims reflect an extension to the exciting direction of the applicant's previou NRSA-supported research. Mechanistic investigation will include the usage of therapeutic IDO- and GITR- immunomodulators, currently in clinical trials for patients, but not specifically for those diagnosed with glioblastoma. The proposed studies aim to investigate translationally- relevant approaches that reverse immunosuppression in glioma, which is the first step to the rational design of effective immunotherapy for patients with incurable brain cancer.
Glioblastoma multiforme is an incurable form of brain cancer with an average survival of 14.6 months post- diagnosis. Recent and exciting work from our laboratory has demonstrated that upregulated expression of the immunomodulatory gene, indoleamine 2,3 dioxygenase (IDO), is associated with a poor prognosis in glioma patients, as well as in pre-clinical models that recapitulate brain tumors;suggesting IDO to be a critical target for future therapeutic consideration. This project aims to extend our previous observations by focusing on the mechanism that induces immunosuppression mediated by the interaction between IDO and Tregs in glioma.