Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Acta Neuropathol Commun. 2022 Feb 10;10(1):19. doi: 10.1186/s40478-022-01323-w.
The tumor micro-environment (TME) plays an important role in various cancers, including gliomas. We estimated immune cell type-specific gene expression profiles in 3 large clinically annotated glioma datasets using CIBERSORTx and LM22/LM10 blood-based immune signatures and found that the proportions and estimated gene expression patterns of specific immune cells significantly varied according to IDH mutation status. When IDH-WT and IDH-MUT tumors were considered separately, cluster-of-cluster analyses of immune cell gene expression identified groups with distinct survival outcomes. We confirmed and extended these findings by applying a signature matrix derived from single-cell RNA-sequencing data derived from 19 glioma tumor samples to the bulk profiling data, validating findings from the LM22/LM10 results. To link immune cell signatures with outcomes in checkpoint therapy, we then showed a significant association of monocytic lineage cell gene expression clusters with patient survival and with mesenchymal gene expression scores. Integrating immune cell-based gene expression with previously described malignant cell states in glioma demonstrated that macrophage M0 abundance significantly correlated with mesenchymal state in IDH-WT gliomas, with evidence of a previously implicated role of the Oncostatin-M receptor and macrophages in the mesenchymal state. Among IDH-WT tumors that were enriched for the mesenchymal cell state, the estimated M0 macrophage expression signature coordinately also trended to a mesenchymal signature. We also examined IDH-MUT tumors stratified by 1p/19q status, showing that a mesenchymal gene expression signature the M0 macrophage fraction was enriched in IDH-MUT, non-codeleted tumors. Overall, these results highlight the biological and clinical significance of the immune cell environment related to IDH mutation status, patient prognosis and the mesenchymal state in diffuse gliomas.
肿瘤微环境（TME）在各种癌症中都起着重要作用，包括神经胶质瘤。我们使用 CIBERSORTx 和基于血液的 LM22/LM10 免疫特征，从 3 个大型临床注释的神经胶质瘤数据集中估计了免疫细胞类型特异性基因表达谱，发现特定免疫细胞的比例和估计的基因表达模式根据 IDH 突变状态而显著变化。当分别考虑 IDH-WT 和 IDH-MUT 肿瘤时，免疫细胞基因表达的簇聚类分析确定了具有不同生存结局的群体。我们通过将源自 19 个神经胶质瘤肿瘤样本的单细胞 RNA-seq 数据的签名矩阵应用于批量分析数据，验证了 LM22/LM10 结果，从而证实并扩展了这些发现。为了将免疫细胞特征与检查点治疗的结果联系起来，我们展示了单核细胞谱系细胞基因表达簇与患者生存和间充质基因表达评分的显著关联。将免疫细胞基于基因表达与神经胶质瘤中先前描述的恶性细胞状态相结合，表明 IDH-WT 神经胶质瘤中巨噬细胞 M0 丰度与间充质状态显著相关，表明 Oncostatin-M 受体和巨噬细胞在间充质状态中的作用。在 IDH-WT 肿瘤中，巨噬细胞 M0 丰度与间充质状态显著相关，而在这些肿瘤中，间充质状态的恶性细胞状态明显富集。在 1p/19q 状态分层的 IDH-MUT 肿瘤中，我们还发现 M0 巨噬细胞分数富集了间充质基因表达特征。总的来说，这些结果强调了与 IDH 突变状态、患者预后和弥漫性神经胶质瘤中间充质状态相关的免疫细胞环境的生物学和临床意义。
