Microglia are effector cells of CD47-SIRPα antiphagocytic axis disruption against glioblastoma
Microglia are effector cells of CD47-SIRPα antiphagocytic axis disruption against glioblastoma
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DOI：
10.1073/pnas.1721434116
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发表时间：
2019-01-15
影响因子：
11.1
通讯作者：
Cheshier, Samuel H.
中科院分区：
文献类型：
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作者：
Hutter, Gregor;Theruvath, Johanna;Cheshier, Samuel H.
多形性胶质母细胞瘤（GBM）是一种高度侵袭性的恶性脑肿瘤，具有致命的结局。肿瘤相关巨噬细胞和小胶质细胞（TAM）已被发现是肿瘤微环境中主要的促肿瘤免疫细胞。因此，GBM中肿瘤相关巨噬细胞和小胶质细胞的调节和再教育被认为是一种有前途的抗肿瘤策略。驻留的小胶质细胞和侵入的巨噬细胞已被证明具有不同的起源和功能。尽管卵黄囊来源的小胶质细胞存在于大脑中，但血液来源的单核细胞仅在肿瘤形成等病理条件下侵入中枢神经系统。我们最近表明，SIRP α-CD 47信号传导轴的破坏主要通过诱导肿瘤吞噬作用而对包括GBM在内的各种脑肿瘤有效。然而，大多数效应归因于从外周募集的巨噬细胞，但脑内小胶质细胞的作用尚不清楚。在这里，我们试图利用一个模型来区分居民的小胶质细胞和外周巨噬细胞的GBM-TAM池，使用原位异种移植，免疫缺陷，和同基因小鼠模型与遗传颜色编码的巨噬细胞（Ccr 2（RFP））和小胶质细胞（Cx 3cr 1（GFP））。我们表明，即使在没有吞噬巨噬细胞（Ccr 2（RFP/RFP）），小胶质细胞是肿瘤细胞吞噬的效应细胞，在抗CD 47封锁。此外，巨噬细胞和小胶质细胞显示出不同的形态和转录变化。重要的是，小胶质细胞的转录谱显示较少的炎症反应，这使它们成为临床应用的有希望的靶点。
Glioblastoma multiforme (GBM) is a highly aggressive malignant brain tumor with fatal outcome. Tumor-associated macrophages and microglia (TAMs) have been found to be major tumor-promoting immune cells in the tumor microenvironment. Hence, modulation and reeducation of tumor-associated macrophages and microglia in GBM is considered a promising antitumor strategy. Resident microglia and invading macrophages have been shown to have distinct origin and function. Whereas yolk sac-derived microglia reside in the brain, blood-derived monocytes invade the central nervous system only under pathological conditions like tumor formation. We recently showed that disruption of the SIRP alpha-CD47 signaling axis is efficacious against various brain tumors including GBM primarily by inducing tumor phagocytosis. However, most effects are attributed to macrophages recruited from the periphery but the role of the brain resident microglia is unknown. Here, we sought to utilize a model to distinguish resident microglia and peripheral macrophages within the GBM-TAM pool, using orthotopically xenografted, immunodeficient, and syngeneic mouse models with genetically color-coded macrophages (Ccr2(RFP)) and microglia (Cx3cr1(GFP)). We show that even in the absence of phagocytizing macrophages (Ccr2(RFP/RFP)), microglia are effector cells of tumor cell phagocytosis in response to anti-CD47 blockade. Additionally, macrophages and microglia show distinct morphological and transcriptional changes. Importantly, the transcriptional profile of microglia shows less of an inflammatory response which makes them a promising target for clinical applications.