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首页> 外文期刊>EBioMedicine >Redefining malignant pleural mesothelioma types as a continuum uncovers immune-vascular interactions
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Redefining malignant pleural mesothelioma types as a continuum uncovers immune-vascular interactions

机译：重新定义恶性胸膜间皮瘤类型作为连续体，揭示免疫-血管相互作用

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Background Malignant Pleural Mesothelioma (MPM) is an aggressive disease related to asbestos exposure, with no effective therapeutic options. Methods We undertook unsupervised analyses of RNA-sequencing data of 284 MPMs, with no assumption of discreteness. Using immunohistochemistry, we performed an orthogonal validation on a subset of 103 samples and a biological replication in an independent series of 77 samples. Findings A continuum of molecular profiles explained the prognosis of the disease better than any discrete model. The immune and vascular pathways were the major sources of molecular variation, with strong differences in the expression of immune checkpoints and pro-angiogenic genes; the extrema of this continuum had specific molecular profiles: a “hot” bad-prognosis profile, with high lymphocyte infiltration and high expression of immune checkpoints and pro-angiogenic genes; a “cold” bad-prognosis profile, with low lymphocyte infiltration and high expression of pro-angiogenic genes; and a “VEGFR2+/VISTA+” better-prognosis profile, with high expression of immune checkpoint VISTA and pro-angiogenic gene VEGFR2 . We validated the gene expression levels at the protein level for a subset of five selected genes belonging to the immune and vascular pathways ( CD8A, PDL1, VEGFR3, VEGFR2 , and VISTA ), in the validation series, and replicated the molecular profiles as well as their prognostic value in the replication series. Interpretation The prognosis of MPM is best explained by a continuous model, which extremes show specific expression patterns of genes involved in angiogenesis and immune response.
机译：背景恶性胸膜间皮瘤（MPM）是与石棉接触有关的侵袭性疾病，没有有效的治疗选择。方法我们对284 MPM的RNA测序数据进行了无监督分析，没有假设离散性。使用免疫组织化学，我们对103个样品的子集进行了正交验证，并在77个样品的独立系列中进行了生物复制。研究结果分子概况的连续性比任何离散模型更好地解释了疾病的预后。免疫和血管途径是分子变异的主要来源，免疫检查点和促血管生成基因的表达差异很大。该连续体的末端具有特定的分子特征：“热”不良预后特征，具有高淋巴细胞浸润以及免疫检查点和促血管生成基因的高表达; “冷”不良预后，淋巴细胞浸润少，促血管生成基因高表达;和“ VEGFR2 + / VISTA +”的预后较好，免疫检查点VISTA和促血管生成基因VEGFR2的表达高。在验证系列中，我们验证了属于免疫和血管通路的五个选定基因（CD8A，PDL1，VEGFR3，VEGFR2和VISTA）的五个子集的蛋白质水平的基因表达水平，并复制了分子图谱以及它们在复制系列中的预后价值。解释连续模型可以最好地解释MPM的预后，该模型极端显示了参与血管生成和免疫反应的基因的特定表达模式。

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