title: Tumor-associated MICA is shed by ADAM proteases.
abstract: The immunoreceptor NKG2D promotes immunosurveillance of malignant cells and protects the host from tumor initiation by activating natural killer cells and costimulating CD8 T cells. NKG2D-mediated recognition of malignant cells by cytotoxic lymphocytes is enabled through the tumor-associated expression of NKG2D ligands (NKG2DL) resulting from cellular or genotoxic stress. Shedding of NKG2DL is thought to constitute a major countermechanism of tumor cells to subvert NKG2D-mediated immunosurveillance. Here, we report that the prototypical NKG2DL MICA is released by proteolytic cleavage in the stalk of the MICA ectodomain, where deletions, but not alanine substitutions, impede MICA shedding. Small compound-mediated stimulation and inhibition of MICA shedding adduced characteristics that indicated an involvement of members of the "a disintegrin and metalloproteinase" (ADAM) family. Accordingly, MICA shedding by tumor cells was inhibited by silencing of the related ADAM10 and ADAM17 proteases, which are known to promote tumor growth by releasing epidermal growth factor receptor ligands. Collectively, our data show that ADAM10 and ADAM17 are critically involved in the tumor-associated proteolytic release of soluble MICA facilitating tumor immune escape. Hence, therapeutic blockade of ADAM10 and ADAM17 seems promising for cancer treatment by targeting both growth and immune escape of tumors.
authors.affiliation: Department of Immunology, Institute for Cell Biology, Eberhard-Karls-University, Tübingen, Germany.
authors.forename: Inja
authors.initials: I
authors.lastname: Waldhauer
authors.forename: Dennis
authors.initials: D
authors.lastname: Goehlsdorf
authors.forename: Friederike
authors.initials: F
authors.lastname: Gieseke
authors.forename: Toni
authors.initials: T
authors.lastname: Weinschenk
authors.forename: Mareike
authors.initials: M
authors.lastname: Wittenbrink
authors.forename: Andreas
authors.initials: A
authors.lastname: Ludwig
authors.forename: Stefan
authors.initials: S
authors.lastname: Stevanovic
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Rammensee
authors.forename: Alexander
authors.initials: A
authors.lastname: Steinle
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D001483:Base Sequence; D017931:DNA Primers; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D015395:Histocompatibility Antigens Class I; C099187:MHC class I-related chain A; D051722:ADAM Proteins