The IDO1 selective inhibitor epacadostat enhances dendritic cell immunogenicity and lytic ability of tumor antigen-specific T cells.
The IDO1 selective inhibitor epacadostat enhances dendritic cell immunogenicity and lytic ability of tumor antigen-specific T cells.
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DOI：
10.18632/oncotarget.9326
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发表时间：
2016-06-21
期刊：
影响因子：
--
通讯作者：
Tsang KY
中科院分区：
文献类型：
--
作者：
Jochems C;Fantini M;Fernando RI;Kwilas AR;Donahue RN;Lepone LM;Grenga I;Kim YS;Brechbiel MW;Gulley JL;Madan RA;Heery CR;Hodge JW;Newton R;Schlom J;Tsang KY
Epacadostat是一种新型吲哚胺-2,3-双加氧酶-1 （IDO1）抑制剂，可抑制全身色氨酸分解代谢，目前正在进行临床试验评估。我们研究了epacadostat对(a)人树突状细胞（dc）的成熟和激活人肿瘤抗原特异性细胞毒性T细胞（CTL）系的能力，以及随后肿瘤细胞的T细胞裂解，(b)人调节性T细胞（Tregs）和(c)体外人外周血单核细胞（PBMCs）的影响。同时使用epacadostat和IFN-γ +脂多糖（LPS）没有改变成熟的人dc的表型，并且如预期的那样减少了色氨酸分解和犬尿氨酸的产生。经肽脉冲DCs刺激的肽特异性t细胞系，如果用epacadostat处理DCs，其产生的IFN-γ、TNFα、GM-CSF和IL-8显著增加。这些T细胞在每个细胞的基础上也显示出更高水平的肿瘤细胞溶解。Epacadostat还显著降低了由IFN-γ + LPS成熟的人dc产生IDO诱导的Treg增殖，尽管Treg表型没有改变。用epacadstat处理人外周血单核细胞，行多色流式细胞术；对123个离散免疫细胞亚群的分析显示，主要免疫细胞类型没有变化，活化的CD83+常规dc增加，未成熟活化的Tim3+ NK细胞减少。这些研究首次显示了epacadostat对人dc的几种影响，以及随后对CTL和treg的影响，并为epacadostat如何潜在地提高免疫疗法（包括癌症疫苗）的疗效提供了理论依据。
Epacadostat is a novel inhibitor of indoleamine-2,3-dioxygenase-1 (IDO1) that suppresses systemic tryptophan catabolism and is currently being evaluated in ongoing clinical trials. We investigated the effects of epacadostat on (a) human dendritic cells (DCs) with respect to maturation and ability to activate human tumor antigen-specific cytotoxic T-cell (CTL) lines, and subsequent T-cell lysis of tumor cells, (b) human regulatory T cells (Tregs), and (c) human peripheral blood mononuclear cells (PBMCs) in vitro. Simultaneous treatment with epacadostat and IFN-γ plus lipopolysaccharide (LPS) did not change the phenotype of matured human DCs, and as expected decreased the tryptophan breakdown and kynurenine production. Peptide-specific T-cell lines stimulated with DCs pulsed with peptide produced significantly more IFN-γ, TNFα, GM-CSF and IL-8 if the DCs were treated with epacadostat. These T cells also displayed higher levels of tumor cell lysis on a per cell basis. Epacadostat also significantly decreased Treg proliferation induced by IDO production from IFN-γ plus LPS matured human DCs, although the Treg phenotype did not change. Multicolor flow cytometry was performed on human PBMCs treated with epacadostat; analysis of 123 discrete immune cell subsets revealed no changes in major immune cell types, an increase in activated CD83+ conventional DCs, and a decrease in immature activated Tim3+ NK cells. These studies show for the first time several effects of epacadostat on human DCs, and subsequent effects on CTL and Tregs, and provide a rationale as to how epacadostat could potentially increase the efficacy of immunotherapeutics, including cancer vaccines.
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影响因子：
4.8
作者：
Astigiano, S;Morandi, B;Frumento, G
通讯作者：
Frumento, G
影响因子：
11.5
作者：
Brandacher, G;Perathoner, A;Amberger, A
通讯作者：
Amberger, A
影响因子：
4.4
作者：
Hwu, P;Du, MX;Young, HA
通讯作者：
Young, HA
DOI：
10.1084/jem.189.9.1363
发表时间：
1999-05-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Munn DH;Shafizadeh E;Attwood JT;Bondarev I;Pashine A;Mellor AL
通讯作者：
Mellor AL
DOI：
10.4049/jimmunol.0903670
发表时间：
2010-09-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Mezrich JD;Fechner JH;Zhang X;Johnson BP;Burlingham WJ;Bradfield CA
通讯作者：
Bradfield CA