Obstructing shedding of the immunostimulatory MHC class I chain-related gene B prevents tumor formation.
OBJECTIVE
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.


METHODS
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.
Wu
Jennifer D
JD
Department of Medicine, University of Washington, 325 9th Avenue, Box 359625, Seattle, WA 98104, USA. wuj@u.washington.edu
Atteridge
Catherine L
CL
Wang
Xuanjun
X
Seya
Tsukasa
T
Plymate
Stephen R
SR
D000818:Animals; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005805:Genes, MHC Class I; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000502:physiology*; D007694:Killer Cells, Natural / Q000166:cytology; D008024:Ligands; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008957:Models, Genetic; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism*
D015395:Histocompatibility Antigens Class I; D008024:Ligands; C098080:MICB antigen; D055655:NK Cell Lectin-Like Receptor Subfamily K