Metalloprotease-mediated tumor cell shedding of B7-H6, the ligand of the natural killer cell-activating receptor NKp30

Cancer Res. 2014 Jul 1;74(13):3429-40. doi: 10.1158/0008-5472.CAN-13-3017. Epub 2014 Apr 29.

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.

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
  • B7-H6 antigen, human
  • 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