Molecular Pathways: Targeting IDO1 and Other Tryptophan Dioxygenases for Cancer Immunotherapy.
Molecular Pathways: Targeting IDO1 and Other Tryptophan Dioxygenases for Cancer Immunotherapy.
复制标题
DOI：
10.1158/1078-0432.ccr-15-0420
复制
发表时间：
2015-12-15
期刊：
影响因子：
--
通讯作者：
Wainwright DA
中科院分区：
文献类型：
--
作者：
Zhai L;Spranger S;Binder DC;Gritsina G;Lauing KL;Giles FJ;Wainwright DA
吲哚胺2，3-双加氧酶1(IDO1)、IDO2和色氨酸2，3-双加氧酶(TDO)组成一个酶家族，催化色氨酸(Trp)分解代谢为犬尿氨酸(Kyn)的第一步也是限速步骤。通过随后的酶反应和自发反应，Kyn进一步转化为含能底物NAD+和ATP，以满足细胞的代谢功能。巧合的是，Trp的耗尽和Kyn的积聚分别被证明诱导效应性T细胞凋亡/功能障碍和免疫抑制调节性T细胞的诱导。与其他免疫检查点类似，IDO1和Tdo被认为是免疫治疗干预的重要靶点。这表现在最近抑制Trp到Kyn途径作为控制免疫抑制的手段的努力的增长。目前正在进行临床试验的抑制剂INCB024360、GDC-0919、吲哚昔莫德和一种基于IDO1多肽的疫苗正在评估其对多种癌症的疗效，包括黑色素瘤、胶质母细胞瘤、非小细胞肺癌、胰腺癌和/或乳腺癌以及转移性疾病。尽管有效的临床级抑制剂发展迅速，但战略问题仍然存在。在这里，我们回顾了目前色氨酸分解代谢的治疗抑制剂的文献状况，临床前和临床上对这些努力的评估，治疗靶向发生的代偿性变化，以及新发现的向该领域提出关键问题的信号特征。鉴于人们对确定IDO1/TDO(以及未知程度的IDO2)如何被用于提高癌症免疫治疗效果的兴趣迅速发展，我们提出了一项简短但全面的分析，解决了关键问题，同时强调了仍有待探索的机制。
Indoleamine 2, 3-dioxygenase 1 (IDO1), IDO2 and tryptophan 2, 3-dioxygenase (TDO) comprise a family of enzymes that catalyze the first- and rate-limiting step associated with the catabolic conversion of tryptophan (Trp) into kynurenine (Kyn). Through subsequent enzymatic and spontaneous reactions, Kyn is further converted into the energetic substrates, NAD+ and ATP to fuel cellular metabolic functions. Coincidently, the depletion of Trp and accumulation of Kyn has been demonstrated to induce effector T cell apoptosis/dysfunction and immunosuppressive regulatory T cell induction, respectively. Similar to other immune checkpoints, IDO1 and TDO are suggested to be important targets for immunotherapeutic intervention. This is represented by the recent growth of efforts to inhibit the Trp to Kyn pathway as a means to control immunosuppression. Inhibitors currently in clinical trials, INCB024360, GDC-0919, Indoximod and an IDO1 peptide-based vaccine, are being evaluated for their efficacy against a wide range of cancers including melanoma, glioblastoma, non-small-cell lung-, pancreatic- and/or breast-cancer, as well as metastatic disease. Despite the rapid development of potent clinical-grade inhibitors, strategic questions remain. Here, we review the state of the literature with respect to current therapeutic inhibitors of tryptophan catabolism, evaluation of those efforts, preclinically and clinically, compensatory changes that occur with therapeutic targeting, as well as newly recognized signaling features that raise critical questions to the field. Given the rapidly evolving interest in determining how IDO1/TDO, and to an unknown extent, IDO2, can be targeted for increasing cancer immunotherapeutic efficacy, we present a brief but comprehensive analysis that addresses critical questions, while highlighting the mechanics that remain to be explored.