胶质母细胞瘤:上调IDO,作为一种适应性免疫耐受机制

Clinical Cancer Research

2017-07-27Article

9.619

影响因子

原标题:浸润性T细胞促进胶质母细胞瘤(GBM)表达IDO1,患者生存期缩短

① 吲哚胺2、3双加氧酶(IDO1)介导免疫抑制;② 采用手术切除GBM、肿瘤基因组图谱、T细胞与GBM共培养、移植GBM的免疫缺陷小鼠模型;③ 原位杂交法检出手术切除标本表达IDO1,GBM IDO1 mRNA水平与溶细胞性和调节性T细胞标志物基因表达正相关,IFN-γ相关T细胞介导的肿瘤内IDO1水平升高,GBM IDO1水平增加与浸润性T细胞正相关,预后差;④ 为提高T细胞介导的疗效,治疗过程中应联合共抑制T细胞介导的IDO1升高。

吲哚胺2 3双加氧酶 免疫治疗 免疫抑制 免疫检查点 调节性T细胞 胶质母细胞瘤(GBM)

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Title:
Infiltrating T cells increase IDO1 expression in glioblastoma and contribute to decreased patient survival

DOI:
10.1158/1078-0432.CCR-17-0120

Abstract & Authors展开

Abstract:
Indoleamine 2,3 dioxygenase 1 (IDO1) mediates potent immunosuppression in multiple preclinical models of cancer. However, the basis for elevated IDO1 expression in human cancer, including the most common primary malignant brain tumor in adults, glioblastoma (GBM), is poorly understood. The major objective of this study is to address this gap in our understanding of how IDO1 expression contributes to the biology of GBM, and whether its level of expression is a determinant of GBM patient outcome.<br /><br />Experimental Design: Patient-resected GBM, the cancer genome atlas, human T cell:GBM co-cultures, as well as nu/nu, NOD-scid and humanized (NSG-SGM3-BLT) mice engrafted human GBM, form the basis of our investigation.<br /><br />Results: In situ hybridization for IDO1 revealed transcript expression throughout patient-resected GBM, whereas immunohistochemical IDO1 positivity was highly variable. Multivariate statistical analysis revealed that higher levels of IDO1 transcript predict a poor patient prognosis (P=0.0076). GBM IDO1 mRNA levels positively correlated with increased gene expression for markers of cytolytic and regulatory T cells, in addition to decreased patient survival. Humanized mice intracranially-engrafted human GBM revealed an IFNg-associated T cell-mediated increase of intratumoral IDO1 <br /><br />Conclusions: Our data demonstrate that high intratumoral IDO1 mRNA levels correlate with a poor GBM patient prognosis. It also confirms the positive correlation between increased GBM IDO1 levels and human-infiltrating T cells. Collectively, this study suggests that future efforts aimed at increasing T cell-mediated effects against GBM, should consider combinatorial approaches that co-inhibit potential T cell-mediated IDO1 enhancement during therapy.

All Authors:
Lijie Zhai,Erik Ladomersky,Kristen L Lauing,Meijing Wu,Matthew Genet,Galina Gritsina,Balázs Győrffy,Priscilla K Brastianos,David Binder,Jeffrey A Sosman,Francis J Giles,C David James,Craig Horbinski,Roger Stupp,Derek A Wainwright

First Authors:
Lijie Zhai

Correspondence:
Derek A Wainwright

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