Cutting edge: down-regulation of MICA on human tumors by proteolytic shedding.
The immunoreceptor NKG2D stimulates tumor immunity through activation of CD8 T cells and NK cells. Its ligand MICA has been shown to be broadly expressed on human tumors of epithelial origin. MICA expression correlates with an enrichment of Vdelta1 T cells in tumor tissue. We report that human tumor cells spontaneously release a soluble form of MICA encompassing the three extracellular domains, which is present at high levels in sera of patients with gastrointestinal malignancies, but not in healthy donors. Release of MICA from tumor cells is blocked by inhibition of metalloproteinases, concomitantly causing accumulation of MICA on the cell surface. Shedding of MICA by tumor cells may modulate NKG2D-mediated tumor immune surveillance. In addition, determination of soluble MICA levels may be implemented as an immunological diagnostic marker in patients with epithelial malignancies.
Salih
Helmut R
HR
Department of Internal Medicine II, University Hospital, Eberhard-Karls-University, Auf der Morgenstelle 15, 72076 Tubingen, Germany.
Rammensee
Hans-Georg
HG
Steinle
Alexander
A
D000818:Animals; D015536:Down-Regulation / Q000276:immunology*; D005770:Gastrointestinal Neoplasms / Q000097:blood / Q000201:enzymology / Q000276:immunology; D019073:HT29 Cells; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D008565:Membrane Proteins / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic / Q000502:physiology; D055607:Receptors, Natural Killer Cell; D014407:Tumor Cells, Cultured
D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; C527086:Klrk1 protein, mouse; C099187:MHC class I-related chain A; D008565:Membrane Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D008666:Metalloendopeptidases