Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
Department of Pathology, Washington University School of Medicine, St. Louis, MO, USA.
Neuro Oncol. 2022 Jan 5;24(1):14-26. doi: 10.1093/neuonc/noab130.
Emerging insights from numerous laboratories have revealed important roles for nonneoplastic cells in the development and progression of brain tumors. One of these nonneoplastic cellular constituents, glioma-associated microglia (GAM), represents a unique population of brain monocytes within the tumor microenvironment that have been reported to both promote and inhibit glioma proliferation. To elucidate the role of GAM in the setting of low-grade glioma (LGG), we leveraged RNA sequencing meta-analysis, genetically engineered mouse strains, and human biospecimens.
Publicly available disease-associated microglia (DAM) RNA-seq datasets were used, followed by immunohistochemistry and RNAScope validation. CD11a-deficient mouse microglia were used for in vitro functional studies, while LGG growth in mice was assessed using anti-CD11a neutralizing antibody treatment of Neurofibromatosis type 1 (Nf1) optic glioma mice in vivo.
We identified Itgal/CD11a enrichment in GAM relative to other DAM populations, which was confirmed in several independently generated murine models of Nf1 optic glioma. Moreover, ITGAL/CD11A expression was similarly increased in human LGG (pilocytic astrocytoma) specimens from several different datasets, specifically in microglia from these tumors. Using CD11a-knockout mice, CD11a expression was shown to be critical for murine microglia CX3CL1 receptor (Cx3cr1) expression and CX3CL1-directed motility, as well as glioma mitogen (Ccl5) production. Consistent with an instructive role for CD11a+ microglia in stromal control of LGG growth, antibody-mediated CD11a inhibition reduced mouse Nf1 LGG growth in vivo.
Collectively, these findings establish ITGAL/CD11A as a critical microglia regulator of LGG biology relevant to future stroma-targeted brain tumor treatment strategies.
众多实验室的新发现揭示了非肿瘤细胞在脑肿瘤发生和进展中的重要作用。这些非肿瘤细胞成分之一，神经胶质瘤相关小胶质细胞（GAM），代表了肿瘤微环境中的一种独特的脑单核细胞群体，据报道，它既能促进也能抑制神经胶质瘤的增殖。为了阐明 GAM 在低级别神经胶质瘤（LGG）中的作用，我们利用了 RNA 测序荟萃分析、基因工程小鼠品系和人类生物样本。
使用了公开的疾病相关小胶质细胞（DAM）RNA 测序数据集，随后进行了免疫组织化学和 RNAScope 验证。使用 CD11a 缺陷型小鼠小胶质细胞进行了体外功能研究，而在体内则使用抗 CD11a 中和抗体治疗神经纤维瘤病 1 型（Nf1）视神经胶质瘤小鼠来评估 LGG 的生长。
我们发现，与其他 DAM 群体相比，GAM 中 Itgal/CD11a 富集，这在几个独立生成的 Nf1 视神经胶质瘤小鼠模型中得到了证实。此外，在来自几个不同数据集的人类 LGG（毛细胞星形细胞瘤）标本中，同样观察到 ITGAL/CD11A 表达增加，特别是在这些肿瘤的小胶质细胞中。使用 CD11a 敲除小鼠，CD11a 表达对于小鼠小胶质细胞 CX3CL1 受体（Cx3cr1）表达和 CX3CL1 导向的运动以及神经胶质瘤有丝分裂原（Ccl5）产生至关重要。与 CD11a+小胶质细胞在 LGG 生长的基质控制中的指导作用一致，抗体介导的 CD11a 抑制减少了体内 Nf1 LGG 的生长。
总之，这些发现确立了 ITGAL/CD11A 作为 LGG 生物学的关键小胶质细胞调节剂，与未来针对肿瘤基质的脑肿瘤治疗策略相关。
