TGF-  and metalloproteinases differentially suppress NKG2D ligand surface expression on malignant glioma cells

Abstract

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 MHC class I-chain-related molecules A and B (MICA/B) and UL16-binding proteins (ULBP) 1-3 are expressed in human brain tumours in vivo, while 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 independently of tumour grade. We further delineate two independent mechanisms that can explain these expression patterns: (i) transforming growth factor-beta (TGF-beta) is upregulated during malignant progression and selectively downregulates MICA, ULBP2 and ULBP4 expression, while MICB, ULBP1 and ULBP3 are unaffected. (ii) Cleavage of MICA and ULBP2 is reduced by inhibition of metalloproteinases (MP), whereas no changes in the expression levels of other NKG2DL were detected. Consequently, NKG2DL-dependent NK cell-mediated lysis is enhanced by depletion of TGF-beta or inhibition of MP. Thus, escape from NKG2D-mediated immune surveillance of malignant gliomas in vivo may be promoted by the inhibition of MICA and ULBP2 expression via an autocrine TGF-beta loop and by MP-dependent shedding from the cell surface. Loss of MICA and ULBP2, in contrast to other NKG2DL, may be particularly important in glioma immune escape, and differential regulation of human NKG2DL expression is part of the immunosuppressive properties of human malignant glioma cells.

Epithelial–Mesenchymal Transition Induces an Antitumor Immune Response Mediated by NKG2D Receptor

“…The paradoxical roles of this cytokine are highlighted in the results presented in this article. Thus, previous works have reported that TGF-b downregulates the expression of NKG2D and its ligands in different tumor types (32)(33)(34). In contrast, our experiments demonstrate that EMT of spontaneously immortalized nonmalignant keratinocytes (HaCaT cells) driven by this cytokine clearly results in a marked increase of NKG2DL expression.…”

NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma

“…20 Suppressive cytokines (such as transforming growth factor (TGF)-b and IL-10) and regulatory T (Treg) cells within tumor microenvironments have been shown to suppress NKG2D and NKp30 expression on NK or CD8 1 T cells and also reduce MICA and ULBP expression on malignant cells. [46][47][48] These cytokines and Treg cells strongly contribute to the tumor's escape from NK cell-mediated anti-tumor immune response.…”

HLA-E contributes to an immune-inhibitory phenotype of glioblastoma stem-like cells

“…This lack of efficacy might be related to immune inhibitory properties of glioblastoma cells facilitating immune evasion (Heimberger and Sampson, 2011). Glioma cells should per se be prone to attack by immune effector cells since they express ligands for activating immune receptors on NK cells or cytotoxic T cells (Dietrich et al, 2011;Eisele et al, 2006;Friese et al, 2003;Friese et al, 2004;Wischhusen et al, 2005). However, an immunosuppressive micromilieu hampers an efficient immune response.…”