gms | German Medical Science

NKG2D ligands (NKG2DL) are expressed by infected and transformed cells. They transmit danger signals to NKG2D-expressing immune cells leading to lysis of NKG2DL-expressing cells. We here report that the NKG2DL MICA/B and ULBP1-3 are expressed in human brain tumors in vivo, whereas expression levels are low or undetectable in normal brain. MICA and ULBP2 expression decrease with increasing WHO grade of malignancy, while MICB and ULBP1 are expressed independent of tumor grade. Using human malignant glioma cells in vitro, two independent mechanisms can be suggested that explain these in vivo expression patterns: (i) Transforming growth factor-beta (TGF-b) is upregulated during malignant progression and selectively down-regulates MICA, ULBP2 and ULBP4 expression as shown by siRNA silencing of TGF-b. In contrast, MICB, ULBP1 and ULBP3 are unaffected by TGF-b. (ii) Cleavage of MICA and ULBP2 is reduced by inhibition of metalloproteinases (MP), whereas no changes in expression levels of other NKG2DL are detected. Consequently, NKG2DL-dependent NK cell-mediated lysis is enhanced either by depletion of TGF-b or by inhibition of metalloproteinases. Thus escape from NKG2D-mediated immune surveillance of malignant gliomas is promoted by the inhibition of MICA and ULBP2 expression via an autocrine TGF-b loop and by metalloproteinase-dependent shedding from the cell surface. These data define an important role for MICA and ULBP2 in glioma immune escape and demonstrate a differential regulation of human NKG2DL expression as part of the immunosuppressive properties of TGF-b and metalloproteinases in human malignant gliomas.