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Published on: November 28, 2015
TGF-beta and metalloproteinases differentially suppress NKG2D ligand surface expression on malignant glioma cells
Günter Eisele1, Jörg Wischhusen, Michel Mittelbronn
1Department of General Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. guenter.eisele@uni-tuebingen.de
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.
Insights
Malignant brain tumors downregulate NKG2D ligands (NKG2DL) like MICA and ULBP2 through TGF-beta and metalloproteinases, enabling immune escape. Inhibiting these pathways enhances anti-tumor immunity.
Area of Science:
- Immunology
- Oncology
- Neuroscience
Background:
- NKG2D ligands (NKG2DL) signal danger to immune cells, triggering lysis of infected or cancerous cells.
- MICA/B and ULBP1-3 are NKG2DLs found on tumor cells, but their expression in brain tumors and regulation is not fully understood.
Purpose of the Study:
- To investigate the expression of NKG2DLs in human brain tumors.
- To identify mechanisms regulating NKGDL expression in gliomas.
- To explore therapeutic strategies targeting NKGDLs for enhanced anti-tumor immunity.
Main Methods:
- Analysis of NKG2DL expression in human brain tumors across different WHO grades.
- Investigating the role of TGF-beta in regulating NKGDL expression.
- Assessing the impact of metalloproteinase inhibition on NKGDL shedding.
- Evaluating the effect of TGF-beta depletion and MP inhibition on NK cell-mediated lysis.
Main Results:
- MICA/B and ULBP1-3 are expressed in brain tumors, with low levels in normal brain.
- MICA and ULBP2 expression inversely correlate with WHO malignancy grade.
- TGF-beta downregulates MICA, ULBP2, and ULBP4, while MICB, ULBP1, and ULBP3 remain unaffected.
- Metalloproteinase inhibition reduces MICA and ULBP2 shedding, enhancing NKGDL-dependent lysis.
Conclusions:
- Malignant gliomas escape NKG2D-mediated immune surveillance via TGF-beta-induced downregulation and metalloproteinase-dependent shedding of MICA and ULBP2.
- Differential regulation of NKG2DLs contributes to the immunosuppressive nature of malignant gliomas.
- Targeting TGF-beta or metalloproteinases may enhance NK cell-mediated anti-glioma immunity.
