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.