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大规模基因芯片分析揭示非霍奇金淋巴瘤免疫逃逸的四个阶段。

Large-scale microarray profiling reveals four stages of immune escape in non-Hodgkin lymphomas.

作者信息

Tosolini Marie, Algans Christelle, Pont Frédéric, Ycart Bernard, Fournié Jean-Jacques

机构信息

Centre de Recherches en Cancérologie de Toulouse, INSERM UMR1037, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France; ERL 5294 CNRS, Toulouse, France; Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse, France; Laboratoire d'Excellence 'TOUCAN', Toulouse, France; Programme Hospitalo-Universitaire en Cancérologie CAPTOR, Toulouse, France; Institut Carnot Lymphome CALYM, Toulouse, France.

Centre de Recherches en Cancérologie de Toulouse, INSERM UMR1037, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France; ERL 5294 CNRS, Toulouse, France.

出版信息

Oncoimmunology. 2016 May 19;5(7):e1188246. doi: 10.1080/2162402X.2016.1188246. eCollection 2016 Jul.

Abstract

Non-Hodgkin B-cell lymphoma (B-NHL) are aggressive lymphoid malignancies that develop in patients due to oncogenic activation, chemo-resistance, and immune evasion. Tumor biopsies show that B-NHL frequently uses several immune escape strategies, which has hindered the development of checkpoint blockade immunotherapies in these diseases. To gain a better understanding of B-NHL immune editing, we hypothesized that the transcriptional hallmarks of immune escape associated with these diseases could be identified from the meta-analysis of large series of microarrays from B-NHL biopsies. Thus, 1446 transcriptome microarrays from seven types of B-NHL were downloaded and assembled from 33 public Gene Expression Omnibus (GEO) datasets, and a method for scoring the transcriptional hallmarks in single samples was developed. This approach was validated by matching scores to phenotypic hallmarks of B-NHL such as proliferation, signaling, metabolic activity, and leucocyte infiltration. Through this method, we observed a significant enrichment of 33 immune escape genes in most diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) samples, with fewer in mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL) samples. Comparing these gene expression patterns with overall survival data evidenced four stages of cancer immune editing in B-NHL: non-immunogenic tumors (stage 1), immunogenic tumors without immune escape (stage 2), immunogenic tumors with immune escape (stage 3), and fully immuno-edited tumors (stage 4). This model complements the standard international prognostic indices for B-NHL and proposes that immune escape stages 3 and 4 (76% of the FL and DLBCL samples in this data set) identify patients relevant for checkpoint blockade immunotherapies.

摘要

非霍奇金B细胞淋巴瘤(B-NHL)是侵袭性淋巴恶性肿瘤,因致癌激活、化疗耐药和免疫逃逸在患者体内发展。肿瘤活检显示,B-NHL经常采用多种免疫逃逸策略,这阻碍了这些疾病中检查点阻断免疫疗法的发展。为了更好地理解B-NHL免疫编辑,我们假设可以通过对来自B-NHL活检的大量微阵列进行荟萃分析,识别与这些疾病相关的免疫逃逸转录特征。因此,从33个公共基因表达综合数据库(GEO)数据集中下载并整合了来自七种B-NHL类型的1446个转录组微阵列,并开发了一种对单个样本中的转录特征进行评分的方法。通过将评分与B-NHL的表型特征(如增殖、信号传导、代谢活性和白细胞浸润)相匹配,验证了该方法。通过这种方法,我们观察到在大多数弥漫性大B细胞淋巴瘤(DLBCL)和滤泡性淋巴瘤(FL)样本中,33个免疫逃逸基因显著富集,而在套细胞淋巴瘤(MCL)和边缘区淋巴瘤(MZL)样本中较少。将这些基因表达模式与总生存数据进行比较,证明了B-NHL中癌症免疫编辑的四个阶段:非免疫原性肿瘤(阶段1)、无免疫逃逸的免疫原性肿瘤(阶段2)、有免疫逃逸的免疫原性肿瘤(阶段3)和完全免疫编辑的肿瘤(阶段4)。该模型补充了B-NHL的标准国际预后指数,并提出免疫逃逸阶段3和4(该数据集中76%的FL和DLBCL样本)可识别适合检查点阻断免疫疗法的患者。

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