Differences in gastric carcinoma microenvironment stratify according to EBV infection intensity: implications for possible immune adjuvant therapy.
Differences in gastric carcinoma microenvironment stratify according to EBV infection intensity: implications for possible immune adjuvant therapy.
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DOI：
10.1371/journal.ppat.1003341
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Flemington EK
中科院分区：
文献类型：
--
作者：
Strong MJ;Xu G;Coco J;Baribault C;Vinay DS;Lacey MR;Strong AL;Lehman TA;Seddon MB;Lin Z;Concha M;Baddoo M;Ferris M;Swan KF;Sullivan DE;Burow ME;Taylor CM;Flemington EK
EB病毒（EBV）与全球约10%的胃癌（EBVaGC）相关。虽然以前的研究提供了EBV和胃癌之间的强有力的联系，这些研究是使用选定的EBV基因探针进行的。使用来自癌症基因组图谱（TCGA）的胃癌RNA-seq数据集队列，我们对胃癌中的EBV基因表达进行了定量和全面评估，并评估了EBV相关的细胞通路改变。在17%的样本中检测到EB病毒转录本，但这些样本的EB病毒覆盖深度差异显着。在具有最高EBV覆盖率的四个样品（hiEBVaGC -高EBV相关胃癌）中，来自BamHI A区域的转录物包含大部分EBV读段。还观察到LMP 2和LMP 1（程度较轻）的表达，这是裂解性复制失败的证据。细胞基因表达的分析表明，相对于表达低或无EBV转录物的样品，在表达高水平EBV转录物的样品中显著的免疫细胞浸润和主要的IFNG应答。尽管有明显的免疫细胞浸润，但在hiEBVaGC样品中观察到高水平的细胞毒性T细胞（CTL）和自然杀伤（NK）细胞抑制剂IDO 1，表明在该亚组中存在活性耐受诱导途径。这些结果证实了在一个单独的队列的21个越南胃癌样本使用qRT-PCR和组织样本使用原位杂交和免疫组化。最后，一组肿瘤抑制因子和候选癌基因在hiEBVaGC中的表达水平低于EBV-低和EBV-阴性胃癌，表明EBV直接调节肿瘤途径。EB病毒（EBV）在全球约10%的胃癌（GC）病例中检出。尽管EBV与胃癌之间存在密切联系，但EBV对EBV相关胃癌中肿瘤环境的贡献尚不清楚。我们对71例胃癌患者的EBV和宿主细胞基因表达进行了全面评估，以将EBV基因（和表达强度）与细胞和微环境变化联系起来。除了发现EBV与下调的肿瘤调节基因相关之外，该研究还揭示了具有高水平EBV基因表达的样品（hiEBVaGC）与具有低或无EBV基因表达的样品相比，显示具有高干扰素-γ（IFNG）表达的免疫细胞浸润升高。尽管有这种免疫姿态增加的证据，hiEBVaGC样品也显示出强效免疫细胞抑制剂IDO 1的表达升高。这一发现可能部分解释了这些病毒相关肿瘤在局部免疫细胞集中时的持久性。重要的是，小分子IDO抑制剂1 MT（1-甲基色氨酸）已显示逆转IDO 1在其他肿瘤中的耐受诱导作用。我们认为，胃癌的EBV-阴性，EBV-低和EBV-高分层可能提供使用IDO 1抑制剂作为辅助治疗hiEBVaGCs的指标值。
Epstein-Barr virus (EBV) is associated with roughly 10% of gastric carcinomas worldwide (EBVaGC). Although previous investigations provide a strong link between EBV and gastric carcinomas, these studies were performed using selected EBV gene probes. Using a cohort of gastric carcinoma RNA-seq data sets from The Cancer Genome Atlas (TCGA), we performed a quantitative and global assessment of EBV gene expression in gastric carcinomas and assessed EBV associated cellular pathway alterations. EBV transcripts were detected in 17% of samples but these samples varied significantly in EBV coverage depth. In four samples with the highest EBV coverage (hiEBVaGC – high EBV associated gastric carcinoma), transcripts from the BamHI A region comprised the majority of EBV reads. Expression of LMP2, and to a lesser extent, LMP1 were also observed as was evidence of abortive lytic replication. Analysis of cellular gene expression indicated significant immune cell infiltration and a predominant IFNG response in samples expressing high levels of EBV transcripts relative to samples expressing low or no EBV transcripts. Despite the apparent immune cell infiltration, high levels of the cytotoxic T-cell (CTL) and natural killer (NK) cell inhibitor, IDO1, was observed in the hiEBVaGCs samples suggesting an active tolerance inducing pathway in this subgroup. These results were confirmed in a separate cohort of 21 Vietnamese gastric carcinoma samples using qRT-PCR and on tissue samples using in situ hybridization and immunohistochemistry. Lastly, a panel of tumor suppressors and candidate oncogenes were expressed at lower levels in hiEBVaGC versus EBV-low and EBV-negative gastric cancers suggesting the direct regulation of tumor pathways by EBV. Epstein-Barr virus (EBV) is detected in roughly 10% of gastric carcinoma (GC) cases worldwide. Despite a strong link between EBV and gastric carcinoma, the contribution of EBV to the tumor environment in EBV associated gastric carcinoma is unclear. We performed a global assessment of EBV and host cell gene expression in gastric carcinoma tumors from 71 patients to link EBV genes (and expression intensities) to cell and microenvironmental changes. In addition to the finding that EBV is associated with down-regulated tumor regulatory genes, this study revealed that samples with high levels of EBV gene expression (hiEBVaGCs) displayed elevated immune cell infiltration with high interferon-gamma (IFNG) expression compared to samples with low or no EBV gene expression. Despite this evidence of increased immune posturing, hiEBVaGC samples also showed elevated expression of the potent immune cell inhibitor, IDO1. This finding may partly explain the persistence of these virus associated tumors in the face of local immune cell concentration. Importantly, the small molecule IDO inhibitor, 1MT (1-methyl Tryptophan), has been shown to reverse the tolerance inducing effects of IDO1 in other tumors. We propose that stratification of gastric carcinomas into EBV-negative, EBV-low and EBV-high may provide indicator value for the use of IDO1 inhibitors as adjuvant therapies against hiEBVaGCs.
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