Department of Oncology, University of Lausanne, 1011 Lausanne, Switzerland.
Ludwig Institute for Cancer Research, 1011 Lausanne, Switzerland.
Sci Transl Med. 2020 Jul 15;12(552). doi: 10.1126/scitranslmed.aaw7843.
Tumor-associated macrophages (TAMs) and microglia (MG) are potent regulators of glioma development and progression. However, the dynamic alterations of distinct TAM populations during the course of therapeutic intervention, response, and recurrence have not yet been fully explored. Here, we investigated how radiotherapy changes the relative abundance and phenotypes of brain-resident MG and peripherally recruited monocyte-derived macrophages (MDMs) in glioblastoma. We identified radiation-specific, stage-dependent MG and MDM gene expression signatures in murine gliomas and confirmed altered expression of several genes and proteins in recurrent human glioblastoma. We found that targeting these TAM populations using a colony-stimulating factor-1 receptor (CSF-1R) inhibitor combined with radiotherapy substantially enhanced survival in preclinical models. Our findings reveal the dynamics and plasticity of distinct macrophage populations in the irradiated tumor microenvironment, which has translational relevance for enhancing the efficacy of standard-of-care treatment in gliomas.
肿瘤相关巨噬细胞（TAMs）和小胶质细胞（MG）是胶质瘤发生和进展的强大调节剂。然而，在治疗干预、反应和复发过程中，不同 TAM 群体的动态变化尚未被充分探索。在这里，我们研究了放射治疗如何改变脑内驻留的 MG 和外周募集的单核细胞衍生的巨噬细胞（MDMs）在胶质母细胞瘤中的相对丰度和表型。我们在鼠胶质母细胞瘤中鉴定了放射治疗特异性、阶段依赖性的 MG 和 MDM 基因表达特征，并在复发性人类胶质母细胞瘤中证实了几个基因和蛋白质的表达改变。我们发现，使用集落刺激因子 1 受体（CSF-1R）抑制剂联合放射治疗靶向这些 TAM 群体，可显著提高临床前模型中的存活率。我们的研究结果揭示了辐照肿瘤微环境中不同巨噬细胞群体的动态和可塑性，这对增强胶质母细胞瘤标准治疗的疗效具有转化意义。
