Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase
Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase
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DOI：
10.1073/pnas.1113873109
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发表时间：
2012-02-14
影响因子：
11.1
通讯作者：
Van den Eynde, Benoit J.
中科院分区：
文献类型：
--
作者：
Pilotte, Luc;Larrieu, Pierre;Van den Eynde, Benoit J.
吲哚胺2，3-双加氧酶（IDO 1）介导的色氨酸催化是外周免疫耐受的重要机制，而IDO 1抑制剂是目前药物开发的热点。色氨酸2，3-双加氧酶（TDO）是一种不相关的肝酶，也可沿犬尿氨酸途径降解色氨酸沿着。在这里，我们表明，酶活性的TDO是在一个显着比例的人类肿瘤中表达。在临床前模型中，肿瘤的TDO表达阻止了免疫小鼠对其的排斥。我们开发了一种TDO抑制剂，其在全身治疗后恢复了小鼠排斥表达TDO的肿瘤的能力。我们的研究结果描述了基于TDO表达的肿瘤免疫抗性的机制，并建立了TDO抑制剂在癌症治疗中的使用的概念验证。
Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO1) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance, and IDO1 inhibition is an active area of drug development. Tryptophan 2,3-dioxygenase (TDO) is an unrelated hepatic enzyme that also degrades tryptophan along the kynurenine pathway. Here, we show that enzymatically active TDO is expressed in a significant proportion of human tumors. In a preclinical model, TDO expression by tumors prevented their rejection by immunized mice. We developed a TDO inhibitor, which, upon systemic treatment, restored the ability of mice to reject TDO-expressing tumors. Our results describe a mechanism of tumoral immune resistance based on TDO expression and establish proof-of-concept for the use of TDO inhibitors in cancer therapy.