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）诱导的强烈免疫抑制，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）作为一个强有力的候选人，是关键参与调节神经胶质瘤诱导的免疫抑制。IDO是一种诱导酶，可将必需氨基酸色氨酸转化为代谢物犬尿氨酸（Kyn.）。临床相关的是，当与表达下调的IDO的神经胶质瘤样本相比时，神经胶质瘤中IDO的上调是预测患者存活率降低的强预后因素（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活性脑肿瘤被显著更多的具有更高GITR表达的调节性T细胞（T细胞; CD 4 + FoxP 3+）浸润。考虑到TdR与GITR在介导Treg功能中的有效免疫抑制功能，我们假设IDO的酶活性的某些方面直接影响Treg稳态。支持这一理论的是最近的 体外研究Kyn相互作用。与CD 4 + T细胞中的芳烃受体（Ahr）的结合导致FoxP 3的表达。基于这些集体观察，我们提出了中心假设：神经胶质瘤衍生的IDO增加Kyn。导致Ahr依赖性Treg扩增和GITR介导的Treg稳定性和/或募集的水平。为了验证这一假设，我们提出：（1）在一种新的胶质瘤转基因模型中证实IDO的相关性，以及（2）研究IDO介导的Kyn的调控。生产-，（3）确定Kyn的影响。Ahr对Treg扩增和免疫抑制的相互作用，以及（4）使用胶质瘤的原位小鼠模型研究GITR在肿瘤内Treg中的作用。具体的目标反映了申请人以前NRSA支持的研究的令人兴奋的方向的延伸。机制研究将包括治疗性IDO和GITR免疫调节剂的使用，目前在患者的临床试验中，但不专门用于诊断为胶质母细胞瘤的患者。拟议的研究旨在研究逆转胶质瘤中免疫抑制的预防相关方法，这是为无法治愈的脑癌患者合理设计有效免疫疗法的第一步。

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.