Laboratory of Molecular Target Therapy for Cancer, Graduate School for Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Center for Comprehensive Community Medicine, Faculty of Medicine, Saga University, Saga, Japan.
PLoS One. 2019 May 10;14(5):e0216825. doi: 10.1371/journal.pone.0216825. eCollection 2019.
Glioma is the most common type of primary brain tumor, accounting for 40% of malignant brain tumors. Although a single gene may not be a marker, an expression profiling and multivariate analyses for cancer immunotherapy must estimate survival of patients. In this study, we conducted expression profiling of immunotherapy-related genes, including those in Th1/2 helper T and regulatory T cells, and stimulatory and inhibitory checkpoint molecules associated with survival prediction in 571 patients with malignant and aggressive form of gliomas, glioblastoma multiforme (GBM). Expression profiling and Random forests analysis of 21 immunosuppressive genes and Kaplan-Meier analysis in 158 patients in the training data set suggested that CD276, also known as B7-H3, could be a single gene marker candidate. Furthermore, prognosis prediction formulas, composed of Th2 cell-related GATA transcription factor 3 (GATA3) and immunosuppressive galactose-specific lectin 3 (LGALS3), based on 67 immunotherapy-related genes showed poor survival with high scores in training data set, which was also validated in another 413 patients in the test data set. The CD276 expression helped distinguish survival curves in the test data set. In addition, inhibitory checkpoint genes, including T cell immunoreceptor with Ig and ITIM domains, V-set domain containing T cell activation inhibitor 1, T-cell immunoglobulin and mucin-domain containing 3, and tumor necrosis factor receptor superfamily 14, showed potential as secondary marker candidates. These results suggest that CD276 expression and the gene signature composed of GATA3 and LGALS3 are effective for prognosis in GBM and will help us understanding target pathways for immunotherapy in GBM.
神经胶质瘤是最常见的原发性脑肿瘤，占恶性脑肿瘤的 40%。虽然单个基因可能不是标志物，但癌症免疫治疗的表达谱和多变量分析必须估计患者的生存情况。在这项研究中，我们对免疫治疗相关基因进行了表达谱分析，包括 Th1/2 辅助 T 细胞和调节性 T 细胞中的基因，以及与生存预测相关的刺激和抑制检查点分子，这些基因在 571 名患有恶性和侵袭性神经胶质瘤（多形性胶质母细胞瘤，GBM）的患者中进行了研究。在训练数据集的 158 名患者中进行了 21 个免疫抑制基因的表达谱和随机森林分析以及 Kaplan-Meier 分析，结果表明 CD276（也称为 B7-H3）可能是一个单基因标志物候选基因。此外，由 Th2 细胞相关的 GATA 转录因子 3（GATA3）和免疫抑制半乳糖特异性凝集素 3（LGALS3）组成的预后预测公式，基于 67 个免疫治疗相关基因，在训练数据集中显示出高评分的不良生存预后，在另一个 413 名测试数据集中也得到了验证。CD276 的表达有助于区分测试数据集中的生存曲线。此外，抑制性检查点基因，包括 T 细胞免疫受体 Ig 和 ITIM 结构域、V 区包含 T 细胞激活抑制剂 1、T 细胞免疫球蛋白和粘蛋白结构域包含 3、肿瘤坏死因子受体超家族 14，具有作为二级标志物候选的潜力。这些结果表明，CD276 表达和由 GATA3 和 LGALS3 组成的基因特征可有效预测 GBM 的预后，并有助于我们了解 GBM 中免疫治疗的靶向途径。
