高级神经胶质母细胞瘤（GBM）是一种恶性程度最高的脑肿瘤，其特点是肿瘤内和肿瘤间的异质性和复杂的肿瘤微环境。为了揭示这种环境中的分子靶点，我们系统地鉴定了具有免疫和结缔组织相互作用的胶质细胞类型水平，并利用来自The Cancer Genome Atlas的GBM患者的RNA测序数据。在高和低免疫和结缔组织评分患者之间的受扰基因经过加权基因共表达网络分析后，确定了免疫和结缔组织浸润患者中胶质细胞类型特异性网络。通过模块内连通性分析，确定了每个模块中具有高连接性的基因。与单变量和多变量预后分析相结合，揭示了免疫和结缔组织浸润患者中的共同关键基因ITGB2，富集于小胶质细胞和新形成的少突胶质细胞。我们发现免疫浸润患者中的以下独特中枢基因：COL6A3（小胶质细胞），ITGAM（少突胶质细胞前体细胞），TNFSF9（小胶质细胞）；在结缔组织浸润患者中，SERPINE1（小胶质细胞）和THBS1（新形成的少突胶质细胞，少突胶质细胞前体细胞）。为了验证这些中枢基因，我们使用了外部GBM患者单细胞RNA测序数据集，发现ITGB2在免疫和结缔组织数据集中明显富集于小胶质细胞、新形成的少突胶质细胞、T细胞、巨噬细胞和脂肪细胞类型。ITGB2的肿瘤浸润分析显示其与髓样树突状细胞、巨噬细胞、单核细胞、中性粒细胞、B细胞、成纤维细胞和脂肪细胞呈相关性。总的来说，对胶质细胞类型的肿瘤微环境成分进行系统筛选，揭示了ITGB2作为原发性GBM的潜在靶点。Copyright © 2023 Elsevier Ltd. All rights reserved.

Glioblastoma multiforme (GBM) is the most aggressive form of brain tumor characterized by inter and intra-tumor heterogeneity and complex tumor microenvironment. To uncover the molecular targets in this milieu, we systematically identified immune and stromal interactions at the glial cell type level that leverages on RNA-sequencing data of GBM patients from The Cancer Genome Atlas. The perturbed genes between the high vs low immune and stromal scored patients were subjected to weighted gene co-expression network analysis to identify the glial cell type specific networks in immune and stromal infiltrated patients. The intramodular connectivity analysis identified the highly connected genes in each module. Combining it with univariable and multivariable prognostic analysis revealed common vital gene ITGB2, between the immune and stromal infiltrated patients enriched in microglia and newly formed oligodendrocytes. We found following unique hub genes in immune infiltrated patients; COL6A3 (microglia), ITGAM (oligodendrocyte precursor cells), TNFSF9 (microglia), and in stromal infiltrated patients, SERPINE1 (microglia) and THBS1 (newly formed oligodendrocytes, oligodendrocyte precursor cells). To validate these hub genes, we used external GBM patient single cell RNA-sequencing dataset and this identified ITGB2 to be significantly enriched in microglia, newly formed oligodendrocytes, T-cells, macrophages and adipocyte cell types in both immune and stromal datasets. The tumor infiltration analysis of ITGB2 showed that it is correlated with myeloid dendritic cells, macrophages, monocytes, neutrophils, B-cells, fibroblasts and adipocytes. Overall, the systematic screening of tumor microenvironment components at glial cell types uncovered ITGB2 as a potential target in primary GBM.Copyright © 2023 Elsevier Ltd. All rights reserved.