The interaction of IDO and Tregs Leads to Immunosuppression in Glioma

描述（由申请人提供）：由于胶质母细胞瘤（GBM）引起的强烈免疫抑制，有效的免疫治疗仍然是一个重大挑战。因此，抑制胶质母细胞瘤诱导的免疫抑制是成功治疗这种致命疾病的关键策略。我们实验室最近的工作已经确定吲哚胺2,3双加氧酶（IDO）是一个强有力的候选酶，它在调节胶质瘤诱导的免疫抑制中起关键作用。IDO是一种诱导酶，可将必需氨基酸色氨酸转化为代谢产物犬尿氨酸。与临床相关的是，与IDO表达下调的胶质瘤标本相比，胶质瘤中IDO表达上调是预测患者生存率降低的一个强有力的预后因素（p<0.005）。此外，我们的初步数据显示，与ido缺陷型脑肿瘤相比，ido激活型脑肿瘤被更多具有更高GITR表达的调节性T细胞（Tregs; CD4+FoxP3+）浸润。鉴于Treg具有强大的免疫抑制功能，结合GITR介导Treg功能，我们假设IDO酶活性的某些方面直接影响Treg的稳态。支持这一理论的是最近的一项研究

DESCRIPTION (provided by applicant): 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.