ABSTRACT
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.
Subject(s)
ADAM Proteins/metabolism , Histocompatibility Antigens Class I/metabolism , Matrix Metalloproteinase 14/metabolism , ADAM Proteins/immunology , Animals , Blotting, Western , Cell Line, Tumor , Cell Separation , Cytotoxicity, Immunologic , Flow Cytometry , Histocompatibility Antigens Class I/immunology , Humans , Immunoprecipitation , Killer Cells, Natural/immunology , Matrix Metalloproteinase 14/immunology , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
PURPOSE: Clinical observations have suggested that shedding of the MHC class I chain-related molecule (MIC) may be one of the mechanisms by which tumors evade host immunosurveillance and progress. However, this hypothesis has never been proven. In this study, we tested this hypothesis using a prostate tumor model and investigated the effect of shedding of MIC on tumor development. EXPERIMENTAL DESIGN: We generated a shedding-resistant noncleavable form of MICB (MICB.A2). We overexpressed MICB.A2, the wild-type MICB, and the recombinant soluble MICB (rsMICB) in mouse prostate tumor TRAMP-C2 (TC2) cells and implanted these cells into severe combined immunodeficient mice. RESULTS: No tumors were developed in animals that were implanted with TC2-MICB.A2 cells, whereas all the animals that were implanted with TC2, TC2-MICB, or TC2-rsMICB cells developed tumors. When a NKG2D-specific antibody CX5 or purified rsMICB was administered to animals before tumor implantation, all animals that were implanted with TC2-MICB.A2 cells developed tumors. In vitro cytotoxicity assay revealed the loss of NKG2D-mediated natural killer cell function in these prechallenged animals, suggesting that persistent levels of soluble MICB in the serum can impair natural killer cell function and thus allow tumor growth. CONCLUSIONS: These data suggest that MIC shedding may contribute significantly to tumor formation by transformed cells and that inhibition of MIC shedding to sustain the NKG2D receptor-MIC ligand recognition may have potential clinical implication in targeted cancer treatment.
