Indoleamine 2,3-Dioxygenase Expression Pattern in the Tumor Microenvironment Predicts Clinical Outcome in Early Stage Cervical Cancer.
Indoleamine 2,3-Dioxygenase Expression Pattern in the Tumor Microenvironment Predicts Clinical Outcome in Early Stage Cervical Cancer.
复制标题
肿瘤微环境中吲哚胺2,3 - 双加氧酶的表达模式可预测早期宫颈癌的临床结局。
DOI：
10.3389/fimmu.2018.01598
复制
发表时间：
2018
影响因子：
7.3
通讯作者：
Jordanova ES
中科院分区：
文献类型：
--
作者：
Heeren AM;van Dijk I;Berry DRAI;Khelil M;Ferns D;Kole J;Musters RJP;Thijssen VL;Mom CH;Kenter GG;Bleeker MCG;de Gruijl TD;Jordanova ES
吲哚胺 2,3-双加氧酶 (IDO) 可将必需氨基酸色氨酸 (trp) 降解为犬尿氨酸 (kyn) 及其衍生物，从而抑制 T 细胞功能，从而充当免疫调节剂。血清中kyn/trp比值是宫颈癌患者的预后因素；然而，关于血清水平与肿瘤中 IDO 表达之间关系的信息尚缺乏。通过各种免疫组织化学 (IHC) 技术（包括 7 色荧光多参数 IHC）研究了 71 个原发性和 14 对转移性宫颈癌样本中的 IDO 表达，并检查了血清中 IDO 代谢物浓度、临床病理特征和（增殖）T 细胞（CD8、Ki67 和 FoxP3）存在之间的联系。此外，我们使用癌症基因组图谱 (TCGA) 发布的 144 个宫颈肿瘤样本的 RNAseq 数据比较了 IDO1 和 IFNG 基因表达与临床参数之间的关系。在这里，我们证明，斑片状肿瘤 IDO 表达与宫颈癌中全身 kyn/trp 比率增加相关 (P = 0.009)，而基质界面的边缘肿瘤表达与改善的无病生存 (DFS) (P = 0.017) 和疾病特异性生存 (P = 0.043) 相关。后者可能与T细胞浸润和局部IFNγ释放诱导IDO表达有关。事实上，对 144 个宫颈肿瘤样本的 TCGA 分析显示，IDO1 和 IFNG mRNA 表达水平之间存在很强的正相关性 (P<0.001)，并且与高 IDO1 和 IFNG 转录水平改善的 DFS 显着相关 (P<0.031)。出乎意料的是，IDO+肿瘤具有更高的CD8+Ki67+T细胞率(P = 0.004)。因此，我们的数据表明，原发性肿瘤样本中的血清kyn/trp比值和IDO表达并不是用于实施IDO抑制剂的临床试验的早期宫颈癌患者的预后和分层的明确生物标志物。相反，肿瘤中边缘的 IDO 表达模式主要预测良好的结果，这可能与宫颈肿瘤微环境中 IFNγ 的释放有关。
The indoleamine 2,3-dioxygenase (IDO) enzyme can act as an immunoregulator by inhibiting T cell function via the degradation of the essential amino acid tryptophan (trp) into kynurenine (kyn) and its derivates. The kyn/trp ratio in serum is a prognostic factor for cervical cancer patients; however, information about the relationship between serum levels and IDO expression in the tumor is lacking. IDO expression was studied in 71 primary and 14 paired metastatic cervical cancer samples by various immunohistochemical (IHC) techniques, including 7-color fluorescent multiparameter IHC, and the link between the concentration of IDO metabolites in serum, clinicopathological characteristics, and the presence of (proliferating) T cells (CD8, Ki67, and FoxP3) was examined. In addition, we compared the relationships between IDO1 and IFNG gene expression and clinical parameters using RNAseq data from 144 cervical tumor samples published by The Cancer Genome Atlas (TCGA). Here, we demonstrate that patchy tumor IDO expression is associated with an increased systemic kyn/trp ratio in cervical cancer (P = 0.009), whereas marginal tumor expression at the interface with the stroma is linked to improved disease-free (DFS) (P = 0.017) and disease-specific survival (P = 0.043). The latter may be related to T cell infiltration and localized IFNγ release inducing IDO expression. Indeed, TCGA analysis of 144 cervical tumor samples revealed a strong and positive correlation between IDO1 and IFNG mRNA expression levels (P < 0.001) and a significant association with improved DFS for high IDO1 and IFNG transcript levels (P = 0.031). Unexpectedly, IDO+ tumors had higher CD8+Ki67+ T cell rates (P = 0.004). Our data thus indicate that the serum kyn/trp ratio and IDO expression in primary tumor samples are not clear-cut biomarkers for prognosis and stratification of patients with early stage cervical cancer for clinical trials implementing IDO inhibitors. Rather, a marginal IDO expression pattern in the tumor dominantly predicts favorable outcome, which might be related to IFNγ release in the cervical tumor microenvironment.
登录
查看更多内容
影响因子：
--
作者：
Heeren AM;de Boer E;Bleeker MC;Musters RJ;Buist MR;Kenter GG;de Gruijl TD;Jordanova ES
通讯作者：
Jordanova ES
影响因子：
51.1
作者：
de Sanjose, Silvia;Quint, Wim G. V.;Xavier Bosch, F.
通讯作者：
Xavier Bosch, F.
影响因子：
8.8
作者：
Holmgaard RB;Zamarin D;Li Y;Gasmi B;Munn DH;Allison JP;Merghoub T;Wolchok JD
通讯作者：
Wolchok JD
影响因子：
30.5
作者：
Fallarino, F;Grohmann, U;Puccetti, P
通讯作者：
Puccetti, P
影响因子：
4.5
作者：
Bjoern, Jon;Iversen, Trine Zeeberg;Svane, Inge Marie
通讯作者：
Svane, Inge Marie