Engagement of tumor cell surface MHC I chain related molecule A (MICA) to NKG2D stimulates NK and T cell anti-tumor 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 anti-tumor immunity. Herein we report that the membrane type matrix metalloproteinase (MT-MMP) MMP14 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 ADAMs 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.
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 withTC2,TC2-MICB, orTC2-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. Expression of murine NKG2D ligands on tumor cells has beenshown to be effective in activating natural killer (NK)-mediated tumor elimination experimentally (1 -4). In murine systems, identified NKG2D ligands include the retinoic acid early inducible family of proteins RAE-1 (1, 2), the minor histocompatibility antigen H60 (1, 2), and the murine ULBPlike transcript 1 (4, 5). Cells expressing these molecules are sensitive to the cytotoxicity of mouse NK cells. Ectopic expression of RAE-1 and H60 results in rejection of tumor cell lines expressing normal levels of MHC I molecule (2 -4). Immunodepletion and other experiments showed that the tumor rejection is due to NK and CD8 T cells (2, 3). NKG2D neutralization in vivo enhances host sensitivity to carcinogeninduced spontaneous tumor initiation (6). These studies have proven the principle function of the NKG2D ligand receptormediated NK cell immunity in tumor rejection.In humans, the MHC class I chain -related molecule MICA and MICB (generally termed as MIC) are the most investigated NKG2D ligands, which were proposed to play roles in tumor rejection (7 -9). MIC is rarely expressed by normal human tissues but induced in most human epithelial tumors (10 -13). Expression of MIC on the tumor cell surface can markedly enhance the sensitivity of tumor cells to NK cells in vitro and has been shown to inhibit the growth of human gliomas or small lung carcinomas in experimental models (14,15). These studies sugge...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.