Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer:: Effect on tumor-infiltrating T cells
Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer:: Effect on tumor-infiltrating T cells
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DOI：
10.1158/1078-0432.ccr-05-1966
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发表时间：
2006-02-15
影响因子：
11.5
通讯作者：
Amberger, A
中科院分区：
文献类型：
--
作者：
Brandacher, G;Perathoner, A;Amberger, A
目的：肿瘤微环境中肿瘤和宿主免疫细胞之间的病理相互作用产生了促进肿瘤生长并保护肿瘤免受免疫攻击的免疫抑制网络。在这项研究中，我们研究了免疫调节酶吲哚胺2，3-双加氧酶（IDO）对这种现象的贡献。实验设计：通过逆转录-PCR分析结直肠癌细胞系中IDO的表达，并通过高压液相色谱法评估功能酶活性。半定量免疫组化方法检测143例大肠癌患者组织中IDO的表达，并与肿瘤浸润T细胞数和临床变量进行相关性分析。结果：体外IDO在大肠癌细胞中的表达和功能酶活性与IFN-γ刺激密切相关。免疫组化评分显示IDO在143例肿瘤标本中的56例（39.2%）高表达，而143例中的87例（60.8%）显示IDO低表达水平。与表达低IDO的组织样品（19.42 +/- 2.50; P = 0.0003）相比，IDO高表达与CD 3+浸润性T细胞（46.02 +/- 7.25）的显著减少相关。此外，IDO高免疫反应性与肝转移的频率显著相关（P = 0.003）。Kaplan-Meier分析显示45个月时生存曲线交叉。多变量考克斯分析显示IDO高表达是一个独立的预后变量（45个月，P = 0.04）。结论：IDO高表达的结直肠肿瘤细胞能够通过局部色氨酸耗竭和产生促凋亡色氨酸催化剂，使某些肿瘤亚群最初避免免疫攻击并击败T细胞的侵袭。因此，IDO显著促进结直肠癌患者的疾病进展和总体存活。
Purpose: The pathologic interactions between tumor and host immune cells within the tumor microenvironment create an immunosuppressive network that promotes tumor growth and protects the tumor from immune attack. In this study, we examined the contribution of the immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) on this phenomenon.Experimental Design: Expression of IDO was analyzed in colorectal cancer cell lines by reverse transcription-PCR and functional enzyme activity was assessed by high-pressure liquid chromatography. Semiquantitative immunohistochemistry was used to evaluate IDO expression in the tissue samples of 143 patients with colorectal carcinoma, and was then correlated with the number of tumor-infiltrating T cells and clinical variables.Results: In vitro IDO expression and functional enzyme activity in colorectal cancer cells was found to be strictly dependent on IFN-gamma stimulation. Immunohistochemical scores revealed IDO-high expression in 56 of 143 (39.2%) tumor specimens, whereas 87 of 143 (60.8%) cases showed low IDO expression levels. IDO-high expression was associated with a significant reduction of CD3+ infiltrating T cells (46.02 +/- 7.25) as compared with tissue samples expressing low IDO (19.42 +/- 2.50; P = 0.0003). Furthermore, IDO-high immunoreactivity significantly correlated with the frequency of liver metastases (P = 0.003). Kaplan-Meier analysis showed the crossing of survival curves at 45 months. By multivariate Cox's analysis, IDO-high expression emerged as an independent prognostic variable (45 months, P = 0.04).Conclusion: IDO-high expression by colorectal tumor cells enables certain cancer subsets to initially avoid immune attack and defeat the invasion of T cells via local tryptophan depletion and the production of proapoptotic tryptophan catabolites. Thus, IDO significantly contributes to disease progression and overall survival in patients with colorectal cancer.