Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses
Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses
复制标题
DOI：
10.1158/0008-5472.can-06-2925
复制
发表时间：
2007-01-15
期刊：
影响因子：
11.2
通讯作者：
Munn, David H.
中科院分区：
文献类型：
--
作者：
Hou, De-Yan;Muller, Alexander J.;Munn, David H.
吲哚胺2，3-双加氧酶（IDO）是一种免疫抑制酶，在许多生物环境中有助于耐受。在癌症中，IDO活性可能有助于促进对肿瘤抗原的获得性耐受。IDO抑制剂1-甲基色氨酸正在开发用于临床试验。然而，1-甲基色氨酸存在于两种具有潜在不同生物学特性的立体异构体中，并且尚不清楚哪种异构体可能更适合于初始开发。在这项研究中，我们提供了证据表明D和L立体异构体在活性方面表现出重要的细胞类型特异性变化。使用纯化的酶和在HeLa细胞为基础的测定中，L异构体是IDO活性的更有效的抑制剂。然而，D异构体在逆转IDO表达树突细胞产生的T细胞抑制方面明显更有效，使用人单核细胞衍生的树突细胞和直接从肿瘤引流淋巴结分离的鼠树突细胞。在体内，当在可移植黑色素瘤和可移植和自体乳腺癌的小鼠模型中进行测试时，D异构体在使用环磷酰胺、紫杉醇或吉西他滨的化学免疫治疗方案中作为抗癌剂更有效。1-甲基-色氨酸的D异构体特异性靶向IDO基因，因为D-1-甲基-色氨酸的抗肿瘤作用在IDO基因破坏的小鼠（IDO敲除小鼠）中完全丧失。总之，我们的发现支持D-1-甲基-色氨酸用于人体试验的适用性，该人体试验旨在评估IDO抑制在联合化学免疫治疗方案的设置中阻断宿主介导的免疫抑制和增强抗肿瘤免疫的效用。
Indoleamine 2,3-dioxygenase (IDO) is an immunusuppressive enzyme that contributes to tolerance in a number of biological settings. In cancer, IDO activity may help promote acquired tolerance to tumor antigens. The IDO inhibitor 1-methyl-tryptophan is being developed for clinical trials. However, 1-methyl-tryptophan exists in two stereoisomers with potentially different biological properties, and it has been unclear which isomer might be preferable for initial development. In this study, we provide evidence that the D and L stereoisomers exhibit important cell type-specific variations in activity. The L isomer was the more potent inhibitor of IDO activity using the purified enzyme and in HeLa cell-based assays. However, the D isomer was significantly more effective in reversing the suppression of T cells created by IDO-expressing dendritic cells, using both human monocyte-derived dendritic cells and murine dendritic cells isolated directly from tumor-draining lymph nodes. In vivo, the D isomer was more efficacious as an anticancer agent in chemo-immunotherapy regimens using cyclophosphamide, paclitaxel, or gemcitabine, when tested in mouse models of transplantable melanoma and transplantable and autochthonous breast cancer. The D isomer of 1-methyl-tryptophan specifically targeted the IDO gene because the antitumor effect of D-1-methyl-tryptophan was completely lost in mice with a disruption of the IDO gene (IDO-knockout mice). Taken together, our findings support the suitability Of D-1-methyl-tryptophan for human trials aiming to assess the utility of IDO inhibition to block host-mediated immunosuppression and enhance antitumor immunity in the setting of combined chemo-immunotherapy regimens.