Tumor-Expressed IDO Recruits and Activates MDSCs in a Treg-Dependent Manner.
Tumor-Expressed IDO Recruits and Activates MDSCs in a Treg-Dependent Manner.
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DOI：
10.1016/j.celrep.2015.08.077
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发表时间：
2015-10-13
期刊：
影响因子：
8.8
通讯作者：
Wolchok JD
中科院分区：
文献类型：
--
作者：
Holmgaard RB;Zamarin D;Li Y;Gasmi B;Munn DH;Allison JP;Merghoub T;Wolchok JD
吲哚胺2,3 - 双加氧酶（IDO）已被描述为肿瘤免疫抑制的一种主要机制，尽管人们对其机制了解甚少。在此，我们发现肿瘤细胞表达IDO会导致肿瘤侵袭性生长以及对T细胞靶向免疫疗法产生抗性。我们证明IDO通过募集和激活髓源性抑制细胞（MDSCs），并依赖调节性T细胞（Tregs）的一种机制，来协调局部和全身性免疫抑制效应。支持这些发现的是，我们发现人黑色素瘤肿瘤中的IDO表达与MDSC浸润密切相关。体内使用选择性IDO抑制剂治疗通过减少肿瘤浸润性MDSCs和Tregs的数量，并消除它们的抑制功能，从而逆转了肿瘤相关的免疫抑制。这些发现确立了IDO与肿瘤微环境中多种活跃的免疫抑制机制之间的重要联系，为将IDO作为免疫抑制的核心调节因子之一进行治疗靶向提供了有力的依据。
IDO介导肿瘤中的免疫抑制，尽管其机制了解甚少。霍尔姆高（Holmgaard）等人证明肿瘤IDO是局部和全身性免疫抑制以及对免疫疗法产生抗性的核心调节因子，它以依赖Tregs的方式通过MDSCs的扩增、募集和激活来进行协调。
Indoleamine 2,3-dioxygenase (IDO) has been described as a major mechanism of immunosuppression in tumors, though the mechanisms of this are poorly understood. Here, we find that expression of IDO by tumor cells results in aggressive tumor growth and resistance to T-cell targeting immunotherapies. We demonstrate that IDO orchestrates local and systemic immunosuppressive effects through recruitment and activation of myeloid-derived suppressor cells (MDSCs), through a mechanism dependent on regulatory T cells (Tregs). Supporting these findings, we find that IDO expression in human melanoma tumors is strongly associated with MDSC infiltration. Treatment with a selective IDO inhibitor in vivo reversed tumor-associated immunosuppression by decreasing numbers of tumor-infiltrating MDSCs and Tregs, and abolishing their suppressive function. These findings establish an important link between IDO and multiple immunosuppressive mechanisms active in the tumor microenvironment, providing a strong rationale for therapeutic targeting IDO as one of the central regulators of immune suppression. IDO mediates immune inhibition in tumors, though the mechanisms of this are poorly understood. Holmgaard et al. demonstrate that tumor IDO is a central regulator of both local and systemic immunosuppression and resistance to immunotherapy, which is orchestrated through expansion, recruitment, and activation of MDSCs in a Treg-dependent manner.
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影响因子：
11.2
作者：
Lesokhin AM;Hohl TM;Kitano S;Cortez C;Hirschhorn-Cymerman D;Avogadri F;Rizzuto GA;Lazarus JJ;Pamer EG;Houghton AN;Merghoub T;Wolchok JD
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Wolchok JD
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影响因子：
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作者：
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通讯作者：
Gabrilovich, Dmitry I.
影响因子：
5.4
作者：
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通讯作者：
Haemmerling, Guenter J.
影响因子：
15.9
作者：
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通讯作者：
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