IDO expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival.
IDO expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival.
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DOI：
10.1158/1078-0432.ccr-12-2130
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发表时间：
2012-11-15
期刊：
影响因子：
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通讯作者：
Lesniak MS
中科院分区：
文献类型：
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作者：
Wainwright DA;Balyasnikova IV;Chang AL;Ahmed AU;Moon KS;Auffinger B;Tobias AL;Han Y;Lesniak MS
多形性胶质母细胞瘤（GBM）是一种侵袭性成人脑肿瘤，预后不良。GBM的一个标志是免疫抑制性和肿瘤促进性CD 4 + FoxP 3 +GITR+调节性T细胞（TCRs）的积累。在这里，我们研究了吲哚胺2，3双加氧酶（IDO）在脑肿瘤中的作用以及对Treg募集的影响。为了确定IDO表达在脑肿瘤中的临床相关性，我们首先将患者存活率与来自切除的胶质瘤标本的IDO表达水平相关联。我们还使用了新的原位和转基因胶质瘤模型来研究IDO如何影响TcR。确定肿瘤来源的和外周IDO表达对Treg募集、GITR表达和长期存活的影响。胶质瘤中IDO表达下调预测患者的预后显著更好。巧合的是，当与IDO-感受态脑肿瘤相比时，IDO -感受态和IDO-缺陷型小鼠均显示出携带IDO-缺陷型脑肿瘤的存活优势。此外，IDO缺陷与脑驻留TdR的显着减少，无论是在原位和转基因小鼠胶质瘤模型。IDO缺乏也与TcB上较低的GITR表达水平相关。有趣的是，IDO缺陷所赋予的长期生存优势在T细胞缺陷小鼠中丧失。这些临床和临床前数据证实，IDO表达增加免疫抑制性T细胞的募集，这导致肿瘤生长。相比之下，IDO缺陷减少Treg募集并增强T细胞介导的肿瘤排斥。因此，这些数据表明IDO介导的免疫抑制在胶质瘤中的关键作用，并支持在脑肿瘤的背景下继续研究IDO-Treg相互作用。
Glioblastoma multiforme (GBM) is an aggressive adult brain tumor with a poor prognosis. One hallmark of GBM is the accumulation of immunosuppressive and tumor-promoting CD4+FoxP3+GITR+ regulatory T cells (Tregs). Here, we investigated the role of indoleamine 2,3 dioxygenase (IDO) in brain tumors and the impact on Treg recruitment. To determine the clinical relevance of IDO expression in brain tumors, we first correlated patient survival to the level of IDO expression from resected glioma specimens. We also used novel orthotopic and transgenic models of glioma to study how IDO affects Tregs. The impact of tumor-derived and peripheral IDO expression on Treg recruitment, GITR expression and long-term survival was determined. Downregulated IDO expression in glioma predicted a significantly better prognosis in patients. Co-incidently, both IDO -competent and -deficient mice showed a survival advantage bearing IDO-deficient brain tumors, when compared to IDO-competent brain tumors. Moreover, IDO-deficiency was associated with a significant decrease in brain-resident Tregs, both in orthotopic and transgenic mouse glioma models. IDO-deficiency was also associated with lower GITR expression levels on Tregs. Interestingly, the long-term survival advantage conferred by IDO-deficiency was lost in T cell-deficient mice. These clinical and pre-clinical data confirm that IDO expression increases the recruitment of immunosuppressive Tregs which leads to tumor outgrowth. In contrast, IDO deficiency decreases Treg recruitment and enhances T cell-mediated tumor rejection. Thus, the data suggest a critical role for IDO-mediated immunosuppression in glioma and supports the continued investigation of IDO-Treg interactions in the context of brain tumors.