Antitumor immunity. A shed NKG2D ligand that promotes natural killer cell activation and tumor rejection

Science. 2015 Apr 3;348(6230):136-9. doi: 10.1126/science.1258867. Epub 2015 Mar 5.

Abstract

Immune cells, including natural killer (NK) cells, recognize transformed cells and eliminate them in a process termed immunosurveillance. It is thought that tumor cells evade immunosurveillance by shedding membrane ligands that bind to the NKG2D-activating receptor on NK cells and/or T cells, and desensitize these cells. In contrast, we show that in mice, a shed form of MULT1, a high-affinity NKG2D ligand, causes NK cell activation and tumor rejection. Recombinant soluble MULT1 stimulated tumor rejection in mice. Soluble MULT1 functions, at least in part, by competitively reversing a global desensitization of NK cells imposed by engagement of membrane NKG2D ligands on tumor-associated cells, such as myeloid cells. The results overturn conventional wisdom that soluble ligands are always inhibitory and suggest a new approach for cancer immunotherapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology*
  • Carrier Proteins / pharmacology
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / immunology*
  • Histocompatibility Antigens Class I / pharmacology
  • Immunologic Surveillance
  • Immunotherapy / methods
  • Killer Cells, Natural / immunology*
  • Ligands
  • Lymphocyte Activation
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / therapy
  • Membrane Proteins
  • Mice
  • NK Cell Lectin-Like Receptor Subfamily K / immunology*
  • Neoplasms / immunology*
  • Neoplasms / therapy
  • Recombinant Proteins / genetics
  • Recombinant Proteins / immunology
  • Recombinant Proteins / pharmacology
  • T-Lymphocytes / immunology

Substances

  • Carrier Proteins
  • Histocompatibility Antigens Class I
  • Ligands
  • Membrane Proteins
  • NK Cell Lectin-Like Receptor Subfamily K
  • Recombinant Proteins
  • UL16 binding protein 1, mouse