The membrane type matrix metalloproteinase MMP14 mediates constitutive shedding of MHC class I chain-related molecule A independent of A disintegrin and metalloproteinases.
Engagement of tumor cell surface MHC class I chain-related molecule A (MICA) to NKG2D stimulates NK and T cell antitumor immunity. Shedding of MICA by tumor cells facilitates tumor immune evasion, which may in part contribute to tumor progression. Thus, elucidating the mechanisms by which tumors shed MIC is of great importance for therapy to reinforce NK and T cell antitumor immunity. In this study, we report that the membrane type matrix metalloproteinase (MMP)14 mediates MICA shedding. Suppression of MMP14 expression blocks MICA shedding. Concomitantly, overexpression of MMP14 enhances MICA shedding. The regulation of MICA shedding by MMP14 is independent of the activity of a disintegrin and metalloproteinases, which have been reported to mediate MICA shedding. Finally, MMP14 expression in MICA-positive tumor cells regulates the sensitivity of tumor cells to NK cell killing. These findings suggest that MMP14 may be a new target for tumor immune therapy.
Liu
Gang
G
Department of Medicine, University of Washington, Seattle, WA 98105.
Atteridge
Catherine L
CL
Wang
Xuanjun
X
Lundgren
Ashley D
AD
Wu
Jennifer D
JD
D051722:ADAM Proteins / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002469:Cell Separation; D003602:Cytotoxicity, Immunologic; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D007694:Killer Cells, Natural / Q000276:immunology; D053511:Matrix Metalloproteinase 14 / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D015395:Histocompatibility Antigens Class I; C099187:MHC class I-related chain A; D051722:ADAM Proteins; D053511:Matrix Metalloproteinase 14