Abstract
Malignant gliomas are intrinsic brain tumors with a dismal prognosis. They are well-adapted to hypoxic conditions and poorly immunogenic. NKG2D is one of the major activating receptors of natural killer (NK) cells and binds to several ligands (NKG2DL). Here we evaluated the impact of miRNA on the expression of NKG2DL in glioma cells including stem-like glioma cells. Three of the candidate miRNA predicted to target NKG2DL were expressed in various glioma cell lines as well as in glioblastomas in vivo: miR-20a, miR-93 and miR-106b. LNA inhibitor-mediated miRNA silencing up-regulated cell surface NKG2DL expression, which translated into increased susceptibility to NK cell-mediated lysis. This effect was reversed by neutralizing NKG2D antibodies, confirming that enhanced lysis upon miRNA silencing was mediated through the NKG2D system. Hypoxia, a hallmark of glioblastomas in vivo, down-regulated the expression of NKG2DL on glioma cells, associated with reduced susceptibility to NK cell-mediated lysis. This process, however, was not mediated through any of the examined miRNA. Accordingly, both hypoxia and the expression of miRNA targeting NKG2DL may contribute to the immune evasion of glioma cells at the level of the NKG2D recognition pathway. Targeting miRNA may therefore represent a novel approach to increase the immunogenicity of glioblastoma.
Highlights
Glioblastomas are intrinsic tumors of the brain with a poor prognosis despite comprehensive therapeutic strategies [1]
We speculated that miRNA contribute to the downregulation of NKG2D recognizes different MHC class I-homologous ligands (NKG2DL) expression on glioma cells
Our findings indicate that NKG2DL are controlled by miRNA in glioma cells, a mechanism which has been described for other tumor cells [10,11,12]
Summary
Glioblastomas are intrinsic tumors of the brain with a poor prognosis despite comprehensive therapeutic strategies [1] They are characterized by diffuse infiltration of the healthy brain, well-adapted to a hypoxic environment and poorly immunogenic, precluding potent anti-tumor immune responses. Overcoming the lack of immunogenicity of glioma cells may help to exploit the immune system as a therapeutic weapon against these tumors. This will only be feasible based on a deeper understanding of the underlying mechanisms that preclude active immune responses. NKG2D recognizes different MHC class I-homologous ligands (NKG2DL), including the MHC class I-chain related molecules A (MICA) and B (MICB) and the UL16binding proteins (ULBP)1-6 [4, 5], which are present on the surface of glioma cells [6]. The NKG2D system is suppressed by transforming growth factor www.impactjournals.com/oncotarget (TGF)-β, a master immunosuppressive cytokine expressed by glioma cells, by at least three mechanisms: TGF-β (i) down-regulates the expression of NKG2D on immune effector cells, (ii) reduces MICA and ULBP2 expression levels on the surface of glioma cells [7,8,9], and promotes NKG2DL protein cleavage from the cell surface in a metalloproteinase-dependent manner [8]
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