Extracellular Matrix Protein Tenascin C Increases Phagocytosis Mediated by CD47 Loss of Function in Glioblastoma.
Extracellular Matrix Protein Tenascin C Increases Phagocytosis Mediated by CD47 Loss of Function in Glioblastoma.
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DOI：
10.1158/0008-5472.can-18-3125
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发表时间：
2019-05-15
期刊：
影响因子：
11.2
通讯作者：
Xia S
中科院分区：
文献类型：
--
作者：
Ma D;Liu S;Lal B;Wei S;Wang S;Zhan D;Zhang H;Lee RS;Gao P;Lopez-Bertoni H;Ying M;Li JJ;Laterra J;Wilson MA;Xia S
胶质母细胞瘤（GBM）被髓源性先天免疫细胞高度浸润，这有助于脑肿瘤微环境（TME）的免疫抑制性质。CD47介导免疫逃逸，因为CD47- sirp α轴阻止巨噬细胞和其他骨髓细胞吞噬肿瘤细胞。在这项研究中，我们在人和小鼠GBM细胞中建立了CD47纯合缺失（CD47 - / -），并研究了消除“不要吃我”信号对肿瘤生长和肿瘤- tme相互作用的影响。CD47敲除（KO）对肿瘤细胞体外增殖没有显著影响，但在共培养中显著增加了巨噬细胞对肿瘤细胞的吞噬作用。与CD47野生型异种移植物相比，来自CD47−/−肿瘤细胞的原位异种移植物生长明显减慢，肿瘤细胞吞噬能力增强，m2样肿瘤相关小胶质细胞/巨噬细胞（TAM）募集增加。CD47 KO在异种移植物中增加肿瘤相关的细胞外基质蛋白tenascin C (TNC)，并在体外进一步研究。CD47功能缺失通过Notch通路介导的机制上调肿瘤细胞中TNC的表达。肿瘤细胞中TNC的缺失促进了体内CD47−/−异种移植物的生长，并减少了TAM的数量。TNC敲低也抑制了共培养CD47−/−肿瘤细胞的吞噬。此外，在人巨噬细胞中，TNC通过toll样受体4 （TLR4）和stat3依赖机制刺激包括TNF-α在内的促炎因子的释放。这些结果揭示了TNC在脑肿瘤生物学免疫调节中的重要作用，并证明了TME细胞外基质在影响脑先天免疫细胞抗肿瘤功能方面的突出作用。
Glioblastomas (GBM) are highly infiltrated by myeloid-derived innate immune cells that contribute to the immunosuppressive nature of the brain tumor microenvironment (TME). CD47 has been shown to mediate immune evasion, as the CD47-SIRPα axis prevents phagocytosis of tumor cells by macrophages and other myeloid cells. In this study, we established CD47 homozygous deletion (CD47−/−) in human and mouse GBM cells and investigated the impact of eliminating the “don’t eat me” signal on tumor growth and tumor-TME interactions. CD47 knockout (KO) did not significantly alter tumor cell proliferation in vitro but significantly increased phagocytosis of tumor cells by macrophages in co-cultures. Compared with CD47 wild type xenografts, orthotopic xenografts derived from CD47−/− tumor cells grew significantly slower with enhanced tumor cell phagocytosis and increased recruitment of M2-like tumor associated microglia/macrophages (TAM). CD47 KO increased tumor-associated extracellular matrix protein tenascin C (TNC) in xenografts, which was further examined in vitro. CD47 loss-of-function upregulated TNC expression in tumor cells via a Notch pathway-mediated mechanism. Depletion of TNC in tumor cells enhanced the growth of CD47−/− xenografts in vivo and decreased the number of TAM. TNC knockdown also inhibited phagocytosis of CD47−/− tumor cells in co-cultures. Furthermore, TNC stimulated release of pro-inflammatory factors including TNF-α via a toll-like receptor 4 (TLR4) and STAT3-dependent mechanism in human macrophage cells. These results reveal a vital role for TNC in immunomodulation in brain tumor biology and demonstrate the prominence of the TME extracellular matrix in affecting the anti-tumor function of brain innate immune cells.