Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
Acta Neuropathol Commun. 2021 Sep 8;9(1):148. doi: 10.1186/s40478-021-01249-9.
It is recognized that the tumor microenvironment (TME) plays a critical role in the biology of cancer. To better understand the role of immune cell components in CNS tumors, we applied a deconvolution approach to bulk DNA methylation array data in a large set of newly profiled samples (n = 741) as well as samples from external data sources (n = 3311) of methylation-defined glial and glioneuronal tumors. Using the cell-type proportion data as input, we used dimensionality reduction to visualize sample-wise patterns that emerge from the cell type proportion estimations. In IDH-wildtype glioblastomas (n = 2,072), we identified distinct tumor clusters based on immune cell proportion and demonstrated an association with oncogenic alterations such as EGFR amplification and CDKN2A/B homozygous deletion. We also investigated the immune cluster-specific distribution of four malignant cellular states (AC-like, OPC-like, MES-like and NPC-like) in the IDH-wildtype cohort. We identified two major immune-based subgroups of IDH-mutant gliomas, which largely aligned with 1p/19q co-deletion status. Non-codeleted gliomas showed distinct proportions of a key genomic aberration (CDKN2A/B loss) among immune cell-based groups. We also observed significant positive correlations between monocyte proportion and expression of PD-L1 and PD-L2 (R = 0.54 and 0.68, respectively). Overall, the findings highlight specific roles of the TME in biology and classification of CNS tumors, where specific immune cell admixtures correlate with tumor types and genomic alterations.
人们认识到肿瘤微环境（TME）在癌症生物学中起着关键作用。为了更好地了解免疫细胞成分在中枢神经系统肿瘤中的作用，我们应用去卷积方法对大量新分析样本（n=741）和来自外部数据源（n=3311）的甲基化定义的神经胶质和神经胶质神经元肿瘤的批量 DNA 甲基化阵列数据进行分析。我们将细胞类型比例数据作为输入，使用降维技术可视化从细胞类型比例估计中出现的样本模式。在 IDH 野生型胶质母细胞瘤（n=2072）中，我们根据免疫细胞比例确定了不同的肿瘤簇，并证明了其与致癌改变（如 EGFR 扩增和 CDKN2A/B 纯合缺失）之间存在关联。我们还研究了 IDH 野生型队列中四种恶性细胞状态（AC 样、OPC 样、MES 样和 NPC 样）在免疫簇特异性分布情况。我们鉴定出 IDH 突变型神经胶质瘤的两个主要基于免疫的亚群，这与 1p/19q 共缺失状态基本一致。非共缺失性神经胶质瘤在基于免疫细胞的组中具有不同比例的关键基因组异常（CDKN2A/B 缺失）。我们还观察到单核细胞比例与 PD-L1 和 PD-L2 表达之间存在显著的正相关（R=0.54 和 0.68）。总的来说，这些发现强调了 TME 在中枢神经系统肿瘤生物学和分类中的特定作用，其中特定的免疫细胞混合物与肿瘤类型和基因组改变相关。
