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.
Copyright © 2015, American Association for the Advancement of Science.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Carrier Proteins / genetics
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Carrier Proteins / immunology*
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Carrier Proteins / pharmacology
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Histocompatibility Antigens Class I / genetics
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Histocompatibility Antigens Class I / immunology*
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Histocompatibility Antigens Class I / pharmacology
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Immunologic Surveillance
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Immunotherapy / methods
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Killer Cells, Natural / immunology*
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Ligands
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Lymphocyte Activation
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Melanoma, Experimental / immunology
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Melanoma, Experimental / therapy
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Membrane Proteins
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Mice
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NK Cell Lectin-Like Receptor Subfamily K / immunology*
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Neoplasms / immunology*
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Neoplasms / therapy
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Recombinant Proteins / genetics
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Recombinant Proteins / immunology
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Recombinant Proteins / pharmacology
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T-Lymphocytes / immunology
Substances
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Carrier Proteins
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Histocompatibility Antigens Class I
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Ligands
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Membrane Proteins
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NK Cell Lectin-Like Receptor Subfamily K
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Recombinant Proteins
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UL16 binding protein 1, mouse