Abstract
Natural killer (NK) cells are potent immune effector cells capable of mediating antitumor responses. Thus, during immunoediting, tumor cell populations evolve strategies to escape NK-cell-mediated recognition. In this study, we report a novel mechanism of immune escape involving tumor cell shedding of B7-H6, a ligand for the activating receptor NKp30 that mediates NK-cell binding and NK-cell-mediated killing. Tumor cells from different cancer entities released B7-H6 by ectodomain shedding mediated by the cell surface proteases "a disintegrin and metalloproteases" (ADAM)-10 and ADAM-17, as demonstrated through the use of pharmacologic inhibitors or siRNA-mediated gene attenuation. Inhibiting this proteolytic shedding process increased the levels of B7-H6 expressed on the surface of tumor cells, enhancing NKp30-mediated activation of NK cells. Notably, we documented elevated levels of soluble B7-H6 levels in blood sera obtained from a subset of patients with malignant melanoma, compared with healthy control individuals, along with evidence of elevated B7-H6 expression in melanoma specimens in situ. Taken together, our results illustrated a novel mechanism of immune escape in which tumor cells impede NK-mediated recognition by metalloprotease-mediated shedding of B7-H6. One implication of our findings is that therapeutic inhibition of specific metalloproteases may help support NK-cell-based cancer therapy.
©2014 American Association for Cancer Research.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
ADAM Proteins / antagonists & inhibitors
-
ADAM Proteins / biosynthesis*
-
ADAM Proteins / genetics
-
ADAM10 Protein
-
ADAM17 Protein
-
Amyloid Precursor Protein Secretases / antagonists & inhibitors
-
Amyloid Precursor Protein Secretases / biosynthesis*
-
Amyloid Precursor Protein Secretases / genetics
-
B7 Antigens* / blood
-
B7 Antigens* / genetics
-
B7 Antigens* / metabolism
-
Cell Line, Tumor
-
Dipeptides / pharmacology
-
HCT116 Cells
-
HeLa Cells
-
Humans
-
Hydroxamic Acids / pharmacology
-
Killer Cells, Natural / immunology*
-
Lymphocyte Activation / immunology
-
MCF-7 Cells
-
Melanoma / blood
-
Melanoma / pathology
-
Membrane Proteins / antagonists & inhibitors
-
Membrane Proteins / biosynthesis*
-
Membrane Proteins / genetics
-
Natural Cytotoxicity Triggering Receptor 3 / immunology
-
Phenylalanine / analogs & derivatives
-
Phenylalanine / pharmacology
-
Protease Inhibitors / pharmacology
-
RNA Interference
-
RNA, Messenger / biosynthesis
-
RNA, Small Interfering
-
Thiophenes / pharmacology
-
Tumor Escape
-
Up-Regulation / drug effects
Substances
-
3-(formylhydroxyamino)-2-(3-phenyl-1-propyl)butanoic acid (2,2-dimethyl-1-methylcarbamoyl-1-propyl)amide
-
B7 Antigens
-
Dipeptides
-
Hydroxamic Acids
-
Membrane Proteins
-
NCR3 protein, human
-
NCR3LG1 protein, human
-
Natural Cytotoxicity Triggering Receptor 3
-
Protease Inhibitors
-
RNA, Messenger
-
RNA, Small Interfering
-
Thiophenes
-
Phenylalanine
-
batimastat
-
marimastat
-
Amyloid Precursor Protein Secretases
-
ADAM Proteins
-
ADAM10 Protein
-
ADAM10 protein, human
-
ADAM17 Protein
-
ADAM17 protein, human