吲哚胺 2, 3-双加氧酶 1 (IDO; IDO1; INDO) 是一种限速酶,可将必需氨基酸色氨酸代谢为下游犬尿氨酸。典型地,色氨酸的代谢消耗和/或犬尿氨酸的积累是定义免疫抑制性 IDO 如何抑制免疫细胞效应功能和/或促进 T 细胞死亡的机制。非规范地,IDO 还通过非酶作用抑制免疫。由于 IDO 靶向化合物主要旨在抑制代谢活性,正如目前评估癌症患者安全性/有效性的众多临床试验所证明的那样,除了最近在 III 期 ECHO-301 试验期间 IDO 酶抑制剂治疗令人失望之外,IDO 非酶效应问题已成为机械和治疗考虑的最前沿。在这里,我们回顾了酶依赖性和非酶依赖性 IDO 介导的免疫抑制,因为它主要与胶质母细胞瘤 (GBM) 相关。成人中最常见和最具侵袭性的原发性脑肿瘤。我们小组最近发现,无论是否存在 GBM,高龄时脑实质中 IDO 水平都会增加,这突出了位于脑肿瘤外部但与肿瘤内的GBM细胞IDO活性。因为它们的潜在价值 成人中最常见和最具侵袭性的原发性脑肿瘤。我们小组最近发现,无论是否存在 GBM,高龄时脑实质中 IDO 水平都会增加,这突出了位于脑肿瘤外部但与肿瘤内的GBM细胞IDO活性。因为它们的潜在价值 成人中最常见和最具侵袭性的原发性脑肿瘤。我们小组最近发现,无论是否存在 GBM,高龄时脑实质中 IDO 水平都会增加,这突出了位于脑肿瘤外部但与肿瘤内的GBM细胞IDO活性。因为它们的潜在价值 强调了位于脑肿瘤外部但与肿瘤内 GBM 细胞 IDO 活性协同作用的中枢神经系统细胞中衰老增加的 IDO 活性之间的免疫抑制协同作用。因为它们的潜在价值 强调了位于脑肿瘤外部但与肿瘤内 GBM 细胞 IDO 活性协同作用的中枢神经系统细胞中衰老增加的 IDO 活性之间的免疫抑制协同作用。因为它们的潜在价值体内在 IDO 的研究中,我们还回顾了当前的转基因动物建模系统,同时强调了我们小组最近创建的三个新结构。这项工作集中在一个中心前提上,即晚期癌症患者的最大免疫治疗功效需要 IDO 酶和非酶中和,目前可用的 IDO 靶向药理学方法尚未充分解决这一问题。
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Immunosuppressive IDO in Cancer: Mechanisms of Action, Animal Models, and Targeting Strategies.
Indoleamine 2, 3-dioxygenase 1 (IDO; IDO1; INDO) is a rate-limiting enzyme that metabolizes the essential amino acid, tryptophan, into downstream kynurenines. Canonically, the metabolic depletion of tryptophan and/or the accumulation of kynurenine is the mechanism that defines how immunosuppressive IDO inhibits immune cell effector functions and/or facilitates T cell death. Non-canonically, IDO also suppresses immunity through non-enzymic effects. Since IDO targeting compounds predominantly aim to inhibit metabolic activity as evidenced across the numerous clinical trials currently evaluating safety/efficacy in patients with cancer, in addition to the recent disappointment of IDO enzyme inhibitor therapy during the phase III ECHO-301 trial, the issue of IDO non-enzyme effects have come to the forefront of mechanistic and therapeutic consideration(s). Here, we review enzyme-dependent and -independent IDO-mediated immunosuppression as it primarily relates to glioblastoma (GBM); the most common and aggressive primary brain tumor in adults. Our group's recent discovery that IDO levels increase in the brain parenchyma during advanced age and regardless of whether GBM is present, highlights an immunosuppressive synergy between aging-increased IDO activity in cells of the central nervous system that reside outside of the brain tumor but collaborate with GBM cell IDO activity inside of the tumor. Because of their potential value for the in vivo study of IDO, we also review current transgenic animal modeling systems while highlighting three new constructs recently created by our group. This work converges on the central premise that maximal immunotherapeutic efficacy in subjects with advanced cancer requires both IDO enzyme- and non-enzyme-neutralization, which is not adequately addressed by available IDO-targeting pharmacologic approaches at this time.