title: Shedding of endogenous MHC class I-related chain molecules A and B from different human tumor entities: heterogeneous involvement of the "a disintegrin and metalloproteases" 10 and 17.
abstract: The interaction of the MHC class I-related chain molecules A and B (MICA and MICB) with the corresponding natural killer group 2, member D (NKG2D) receptor triggers cytotoxic effector activity of natural killer cells and certain T-cell subsets and provides a costimulatory signal for cytokine production. Thus, the presence of MICA/B on transformed cells contributes to tumor immunosurveillance. Consequently, the proteolytic cleavage of MICA/B is regarded as an important immune escape mechanism of various cancer cells. To investigate the molecular machinery responsible for the shedding of endogenous MICA/B, we analyzed different human tumor entities including mammary, pancreatic and prostate carcinomas. Flow cytometry and enzyme-linked immunosorbent assay (ELISA) revealed that all tested tumor cells constitutively expressed MICA and MICB on the cell surface and also released NKG2D ligands into the supernatant. We demonstrate that the "a disintegrin and metalloproteases" (ADAMs) 10 and 17 are largely responsible for the generation of soluble MICA/B. Pharmacological inhibition of metalloproteases reduced the level of released MICA/B and increased cell surface expression. Studies using RNA interference not only revealed a prominent role of ADAM10 and ADAM17 in NKG2D ligand shedding but also a tumor cell-specific role of ADAM10 and/or ADAM17 in shedding of MICA or MICB. Moreover, we report that in the prostate carcinoma cell line PC-3, MICA was not shed at all but rather was secreted in exosomes. These data indicate that the release of NKG2D ligands from individual tumor entities is by far more complex than suggested in previously reported MICA/B transfection systems.
authors.affiliation: Institute of Immunology, Christian-Albrechts-University Kiel, Kiel, Germany.
authors.forename: Guranda
authors.initials: G
authors.lastname: Chitadze
authors.forename: Marcus
authors.initials: M
authors.lastname: Lettau
authors.forename: Jaydeep
authors.initials: J
authors.lastname: Bhat
authors.forename: Daniela
authors.initials: D
authors.lastname: Wesch
authors.forename: Alexander
authors.initials: A
authors.lastname: Steinle
authors.forename: Daniel
authors.initials: D
authors.lastname: Fürst
authors.forename: Joannis
authors.initials: J
authors.lastname: Mytilineos
authors.forename: Holger
authors.initials: H
authors.lastname: Kalthoff
authors.forename: Ottmar
authors.initials: O
authors.lastname: Janssen
authors.forename: Hans-Heinrich
authors.initials: HH
authors.lastname: Oberg
authors.forename: Dieter
authors.initials: D
authors.lastname: Kabelitz
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis; D004151:Dipeptides / Q000494:pharmacology; D055354:Exosomes; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007157:Immunologic Surveillance; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000276:immunology / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D016176:T-Lymphocyte Subsets / Q000276:immunology; D060245:Tetraspanin 29 / Q000378:metabolism; D019139:Tumor Escape / Q000276:immunology
chemical_list: D016207:Cytokines; D004151:Dipeptides; D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; C098080:MICB antigen; D061965:Matrix Metalloproteinase Inhibitors; D008565:Membrane Proteins; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D055655:NK Cell Lectin-Like Receptor Subfamily K; D034741:RNA, Small Interfering; D060245:Tetraspanin 29; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human
keywords: ADAM10; ADAM17; MICA; MICB; NKG2D ligands; shedding