CSF-1R inhibition alters macrophage polarization and blocks glioma progression.
CSF-1R inhibition alters macrophage polarization and blocks glioma progression.
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多形性胶质母细胞瘤（GBM）包含几种分子亚型，包括前神经元型GBM。大多数针对胶质瘤细胞的治疗方法都失败了。一种替代策略是针对胶质瘤微环境中的细胞，比如肿瘤相关巨噬细胞和小胶质细胞（TAMs）。巨噬细胞的分化和存活依赖集落刺激因子（CSF）-1。在一种小鼠前神经元型GBM模型中，使用一种CSF - 1R抑制剂来针对TAMs，这显著提高了存活率，并使已形成的肿瘤消退。CSF - 1R阻断还减缓了源自患者的胶质瘤异种移植物在颅内的生长。令人惊讶的是，在接受治疗的小鼠中TAMs并未耗尽。相反，包括粒细胞 - 巨噬细胞集落刺激因子（GM - CSF）和干扰素 - γ在内的胶质瘤分泌因子在CSF - 1R被抑制的情况下促进了TAM的存活。在存活的TAMs中，替代激活的/M2巨噬细胞标志物减少，这与肿瘤促进功能受损相符。这些基因特征与前神经元型GBM患者存活率提高相关。我们的研究结果确定TAMs是前神经元型胶质瘤一个有希望的治疗靶点，并确立了CSF - 1R抑制对GBM的转化潜力。
Glioblastoma multiforme (GBM) comprises several molecular subtypes including proneural GBM. Most therapeutic approaches targeting glioma cells have failed. An alternative strategy is to target cells in the glioma microenvironment, such as tumor-associated macrophages and microglia (TAMs). Macrophages depend upon colony stimulating factor (CSF)-1 for differentiation and survival. A CSF-1R inhibitor was used to target TAMs in a mouse proneural GBM model, which dramatically increased survival, and regressed established tumors. CSF-1R blockade additionally slowed intracranial growth of patient-derived glioma xenografts. Surprisingly, TAMs were not depleted in treated mice. Instead, glioma-secreted factors including GM-CSF and IFN-γ facilitated TAM survival in the context of CSF-1R inhibition. Alternatively activated/ M2 macrophage markers decreased in surviving TAMs, consistent with impaired tumor-promoting functions. These gene signatures were associated with enhanced survival in proneural GBM patients. Our results identify TAMs as a promising therapeutic target for proneural gliomas, and establish the translational potential of CSF-1R inhibition for GBM.
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影响因子：
30.3
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