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The nonclassical MHC class I molecule HLA-E is the only known ligand for CD94/NKG2A and CD94/NKG2C expressed on NK and CD8+ αβ and γδ T cells. HLA-E may transmit either activating signals via CD94/NKG2C or inhibitory signals mediated by CD94/NKG2A. Here we show that HLA-E is expressed at mRNA and protein level in human long-term glioma cell lines, primary ex vivo polyclonal glioblastoma cell cultures and surgical glioblastoma specimens. Furthermore, immunohistochemistry revealed an enhanced in vivo expression of HLA-E in gliomas of lower grades and a massive overexpression in grade IV glioblastomas compared with normal CNS tissue. An immune-inhibitory effect of HLA-E on tumor-specific CTL has already been described. We show that siRNA-mediated silencing of HLA-E or blocking of CD94/NKG2A enables NKG2D-mediated lysis of 51Cr-labeled tumor cells by NK cells. Thus, our study provides the first evidence that expression and interaction of HLA-E on cancer cells with CD94/NKG2A expressed on lymphocytes compromises innate anti-tumor immune responses.