A disintegrin and metalloproteinases 10 and 17 modulate the immunogenicity of glioblastoma-initiating cells
A disintegrin and metalloproteinases 10 and 17 modulate the immunogenicity of glioblastoma-initiating cells
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DOI：
10.1093/neuonc/not232
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发表时间：
2014-03-01
期刊：
影响因子：
15.9
通讯作者：
Eisele, Guenter
中科院分区：
文献类型：
--
作者：
Wolpert, Fabian;Tritschler, Isabel;Eisele, Guenter
背景有新的报道，解整合素和金属蛋白酶（ADAM）家族参与胶质母细胞瘤恶性表型的维持。值得注意的是，ADAM蛋白酶10和17可能通过活化免疫受体NKG2D从细胞表面切割其配体来损害神经胶质瘤细胞的免疫识别。具有干细胞特性的胶质母细胞瘤起始细胞（GIC）已被鉴定为免疫治疗的有吸引力的靶点。然而，GIC免疫原性似乎是低的。在这里，我们表明，ADAM10和ADAM17在GIC的细胞表面上表达，并有助于通过切割ULBP2的免疫抑制表型。在阻断ADAM 10和ADAM 17后，ULBP2的细胞表面表达增强，并且用ADAM 10和ADAM 17特异性抑制剂处理导致自然杀伤细胞对GIC的免疫识别增强。因此，ADAM 10和ADAM 17构成了增强针对GIC的免疫应答的合适靶标。
Background. There are emerging reports that the family of a disintegrin and metalloproteinases (ADAM) are involved in the maintenance of the malignant phenotype of glioblastomas. Notably, ADAM proteases 10 and 17 might impair the immune recognition of glioma cells via the activating immunoreceptor NKG2D by cleavage of its ligands from the cell surface. Glioblastoma-initiating cells (GIC) with stemcell properties have been identified as an attractive target for immunotherapy. However, GIC immunogenicity seems to be low.Methods and Results. Here, we show that ADAM10 and ADAM17 are expressed on the cell surface of GIC and contribute to an immunosuppressive phenotype by cleavage of ULBP2. The cell surface expression of ULBP2 is enhanced upon blocking ADAM10 and ADAM17, and treatment with ADAM10 and ADAM17 specific inhibitors leads to enhanced immunerecognition of GIC by natural killer cells.Conclusions. Therefore, ADAM10 and ADAM17 constitute suitable targets to boost an immune response against GIC.