Glioblastoma (GBM) is the most aggressive malignant primary brain tumor in adults, with a median survival of 14.6 months. Recent efforts have focused on identifying clinically relevant subgroups to improve our understanding of pathogenetic mechanisms and patient stratification. Concurrently, the role of immune cells in the tumor microenvironment has received increasing attention, especially T cells and tumor-associated macrophages (TAM). The latter are a mixed population of activated brain-resident microglia and infiltrating monocytes/monocyte-derived macrophages, both of which express ionized calcium-binding adapter molecule 1 (IBA1). This study investigated differences in immune cell subpopulations among distinct transcriptional subtypes of GBM. Human GBM samples were molecularly characterized and assigned to Proneural, Mesenchymal or Classical subtypes as defined by NanoString nCounter Technology. Subsequently, we performed and analyzed automated immunohistochemical stainings for TAM as well as specific T cell populations. The Mesenchymal subtype of GBM showed the highest presence of TAM, CD8+, CD3+ and FOXP3+ T cells, as compared to Proneural and Classical subtypes. High expression levels of the TAM-related gene AIF1, which encodes the TAM-specific protein IBA1, correlated with a worse prognosis in Proneural GBM, but conferred a survival benefit in Mesenchymal tumors. We used our data to construct a mathematical model that could reliably identify Mesenchymal GBM with high sensitivity using a combination of the aforementioned cell-specific IHC markers. In conclusion, we demonstrated that molecularly distinct GBM subtypes are characterized by profound differences in the composition of their immune microenvironment, which could potentially help to identify tumors amenable to immunotherapy.

中文翻译：

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与间质性和经典性肿瘤相比，人间质性胶质母细胞瘤的特征是免疫细胞的存在增加。

胶质母细胞瘤（GBM）是成人中最具侵略性的恶性原发性脑肿瘤，中位生存期为14.6个月。最近的工作集中在确定临床上相关的亚组，以增进我们对致病机制和患者分层的了解。同时，免疫细胞在肿瘤微环境中的作用越来越受到关注，特别是T细胞和肿瘤相关巨噬细胞（TAM）。后者是活化的大脑驻留小胶质细胞和浸润的单核细胞/单核细胞衍生的巨噬细胞的混合种群，两者均表达离子化的钙结合衔接分子1（IBA1）。这项研究调查了GBM不同转录亚型之间免疫细胞亚群的差异。对人GBM样本进行了分子表征，并分配给Proneural，NanoString nCounter技术定义的间充质或经典亚型。随后，我们进行并分析了TAM以及特定T细胞群体的自动化免疫组织化学染色。与Proneural和Classical亚型相比，GBM的间充质亚型显示出最高的TAM，CD8 +，CD3 +和FOXP3 + T细胞。TAM相关基因AIF1的高表达水平编码TAM特异性蛋白IBA1，与前神经GBM的预后较差有关，但在间质肿瘤中具有生存优势。我们使用我们的数据构建了一个数学模型，可以结合使用上述细胞特异性IHC标记物，以高灵敏度可靠地鉴定间充质GBM。结论，