CD276 and the gene signature composed of GATA3 and LGALS3 enable prognosis prediction of glioblastoma multiforme

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.胶质瘤（Glioma）是最常见的原发性脑肿瘤类型，占恶性脑肿瘤的40%。尽管单一基因未必可作为标志物，但针对癌症免疫治疗的表达谱分析与多变量分析仍需对患者的生存情况进行评估。本研究针对571例恶性侵袭性胶质瘤（多形性胶质母细胞瘤，glioblastoma multiforme, GBM）患者，开展了免疫治疗相关基因的表达谱分析，所涉基因包括Th1/2辅助T细胞、调节性T细胞相关基因，以及与生存预测相关的共刺激与共抑制检查点分子。对训练数据集内158例患者的21个免疫抑制基因进行表达谱分析与随机森林（Random forests）分析，并结合Kaplan-Meier分析后发现，CD276（又名B7-H3）可作为单一基因标志物候选者。此外，基于67个免疫治疗相关基因构建的预后预测模型，由Th2细胞相关的GATA转录因子3（GATA transcription factor 3, GATA3）与免疫抑制性半乳糖特异性凝集素3（galactose-specific lectin 3, LGALS3）组成，在训练数据集中，高分者的生存结局更差；该结果在测试数据集的413例患者中得到了验证。CD276的表达水平可在测试数据集中有效区分患者的生存曲线。此外，包括Ig和ITIM结构域T细胞免疫受体、含V-set结构域T细胞活化抑制因子1、含T细胞免疫球蛋白及黏蛋白结构域3以及肿瘤坏死因子受体超家族14在内的共抑制检查点基因，也展现出作为次级标志物候选者的潜力。上述结果表明，CD276的表达水平以及由GATA3和LGALS3组成的基因特征，可有效预测多形性胶质母细胞瘤患者的预后，有助于阐明多形性胶质母细胞瘤免疫治疗的潜在靶点通路。