Division of Neurosurgery, Department of Surgery, St. Michael's Hospital, Toronto, ON, Canada.
Sci Rep. 2020 Nov 11;10(1):19542. doi: 10.1038/s41598-020-76657-3.
Tumor-associated macrophages (TAMs) constitute up to 50% of tumor bulk in glioblastoma (GBM) and play an important role in tumor maintenance and progression. The recently discovered differences between invading tumour periphery and hypoxic tumor core implies that macrophage biology is also distinct by location. This may provide further insight into the observed treatment resistance to immune modulation. We hypothesize that macrophage activation occurs through processes that are distinct in tumor periphery versus core. We therefore investigated regional differences in TAM recruitment and evolution in GBM by combining open source single cell and bulk gene expression data. We used single cell gene expression data from 4 glioblastomas (total of 3589 cells) and 122 total bulk samples obtained from 10 different patients. Cell identity, ontogeny (bone-marrow derived macrophages-BMDM vs microglia), and macrophage activation state were inferred using verified gene expression signatures. We captured the spectrum of immune states using cell trajectory analysis with pseudotime ordering. In keeping with previous studies, TAMs carrying BMDM identity were more abundant in tumor bulk while microglia-derived TAMs dominated the tumor periphery across all macrophage activation states including pre-activation. We note that core TAMs evolve towards a pro-inflammatory state and identify a subpopulation of cells based on a gene program exhibiting strong, opposing correlation with Programmed cell Death-1 (PD-1) signaling, which may correlate to their response to PD-1 inhibition. By contrast, peripheral TAMs evolve towards anti-inflammatory phenotype and contains a population of cells strongly associated with NFkB signaling. Our preliminary analysis suggests important regional differences in TAMs with regard to recruitment and evolution. We identify regionally distinct and potentially actionable cell subpopulations and advocate the need for a multi-targeted approach to GBM therapeutics.
肿瘤相关巨噬细胞（TAMs）构成胶质母细胞瘤（GBM）肿瘤块的 50%，在肿瘤维持和进展中发挥重要作用。最近发现的侵袭性肿瘤周边和缺氧肿瘤核心之间的差异表明，巨噬细胞生物学也因其位置而不同。这可能为观察到的免疫调节治疗耐药提供进一步的见解。我们假设巨噬细胞的激活是通过在肿瘤周边和核心中不同的过程发生的。因此，我们通过结合开源单细胞和批量基因表达数据来研究 GBM 中 TAM 的募集和演变的区域差异。我们使用了来自 4 个胶质母细胞瘤（共 3589 个细胞）的单细胞基因表达数据和来自 10 个不同患者的 122 个总批量样本。使用经过验证的基因表达特征推断细胞身份、发生（骨髓衍生的巨噬细胞-BMDM 与小胶质细胞）和巨噬细胞激活状态。我们使用具有伪时间排序的细胞轨迹分析来捕获免疫状态的范围。与之前的研究一致，携带 BMDM 身份的 TAMs 在肿瘤块中更为丰富，而小胶质细胞衍生的 TAMs 在所有巨噬细胞激活状态下（包括前激活状态）都主导着肿瘤周边。我们注意到核心 TAMs 向促炎状态进化，并根据表现出与程序性细胞死亡-1（PD-1）信号强烈、相反相关的基因程序识别出一个亚群细胞，这可能与它们对 PD-1 抑制的反应有关。相比之下，外周 TAMs 向抗炎表型进化，并包含一个与 NFkB 信号强烈相关的细胞群体。我们的初步分析表明，TAMs 在招募和演变方面存在重要的区域差异。我们确定了具有区域差异的、潜在可操作的细胞亚群，并主张需要针对 GBM 治疗的多靶点方法。
