通过抑制色氨酸 2,3-双加氧酶逆转肿瘤免疫抵抗。
Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase.
机构信息
Ludwig Institute for Cancer Research, Brussels Branch, and de Duve Institute, Université Catholique de Louvain, B-1200 Brussels, Belgium.
出版信息
Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):2497-502. doi: 10.1073/pnas.1113873109. Epub 2012 Jan 30.
Abstract
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.
摘要
色氨酸分解代谢由吲哚胺 2,3-双加氧酶（IDO1）介导，是导致肿瘤免疫抵抗的外周免疫耐受的重要机制，IDO1 抑制是药物开发的活跃领域。色氨酸 2,3-双加氧酶（TDO）是一种不相关的肝酶，也沿着犬尿氨酸途径降解色氨酸。在这里，我们表明，具有酶活性的 TDO 在很大比例的人类肿瘤中表达。在临床前模型中，肿瘤中 TDO 的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，全身性治疗后，恢复了小鼠排斥表达 TDO 的肿瘤的能力。我们的结果描述了基于 TDO 表达的肿瘤免疫抵抗机制，并为在癌症治疗中使用 TDO 抑制剂建立了概念验证。
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本文引用的文献
1
An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor.一种人类芳香烃受体的内源性肿瘤促进配体。
Nature. 2011 Oct 5;478(7368):197-203. doi: 10.1038/nature10491.
2
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J Med Chem. 2011 Aug 11;54(15):5320-34. doi: 10.1021/jm2006782. Epub 2011 Jul 18.
3
Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.依匹单抗联合达卡巴嗪治疗未经治疗的转移性黑色素瘤。
N Engl J Med. 2011 Jun 30;364(26):2517-26. doi: 10.1056/NEJMoa1104621. Epub 2011 Jun 5.
4
Melanoma drug wins US approval.黑色素瘤药物获美国批准。
Nature. 2011 Mar 31;471(7340):561. doi: 10.1038/471561a.
5
Treating cancer by targeting the immune system.通过靶向免疫系统治疗癌症。
N Engl J Med. 2010 Aug 19;363(8):779-81. doi: 10.1056/NEJMe1006416.
6
New therapies for castration-resistant prostate cancer.去势抵抗性前列腺癌的新疗法。
N Engl J Med. 2010 Jul 29;363(5):479-81. doi: 10.1056/NEJMe1006300.
7
Sipuleucel-T immunotherapy for castration-resistant prostate cancer.西普利单抗免疫治疗去势抵抗性前列腺癌。
N Engl J Med. 2010 Jul 29;363(5):411-22. doi: 10.1056/NEJMoa1001294.
8
Control of immune response by amino acid metabolism.氨基酸代谢对免疫应答的调控。
Immunol Rev. 2010 Jul;236:243-64. doi: 10.1111/j.1600-065X.2010.00915.x.
9
Sipuleucel-T.西普列尤斯-T
Nat Rev Drug Discov. 2010 Jul;9(7):513-4. doi: 10.1038/nrd3220.
10
Improved survival with ipilimumab in patients with metastatic melanoma.Ipilimumab 改善转移性黑色素瘤患者的生存。
N Engl J Med. 2010 Aug 19;363(8):711-23. doi: 10.1056/NEJMoa1003466. Epub 2010 Jun 5.
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