Antitumor immunity. A shed NKG2D ligand that promotes natural killer cell activation and tumor rejection.
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.
Department of Molecular and Cell Biology, and Cancer Research Laboratory, University of California at Berkeley, Berkeley, CA 94720, USA.
Weiwen
W
Deng
Department of Molecular and Cell Biology, and Cancer Research Laboratory, University of California at Berkeley, Berkeley, CA 94720, USA.
Benjamin G
BG
Gowen
Department of Molecular and Cell Biology, and Cancer Research Laboratory, University of California at Berkeley, Berkeley, CA 94720, USA.
Li
L
Zhang
Department of Molecular and Cell Biology, and Cancer Research Laboratory, University of California at Berkeley, Berkeley, CA 94720, USA.
Lin
L
Wang
Department of Molecular and Cell Biology, and Cancer Research Laboratory, University of California at Berkeley, Berkeley, CA 94720, USA.
Stephanie
S
Lau
Department of Molecular and Cell Biology, and Cancer Research Laboratory, University of California at Berkeley, Berkeley, CA 94720, USA.
Alexandre
A
Iannello
Department of Molecular and Cell Biology, and Cancer Research Laboratory, University of California at Berkeley, Berkeley, CA 94720, USA.
Jianfeng
J
Xu
Center for Proteomics University of Rijeka Faculty of Medicine Brace Branchetta 20, 51000 Rijeka, Croatia.
Tihana L
TL
Rovis
Department of Veterinary and Biomedical Sciences, Pennsylvania State University, 115 Henning Building, University Park, PA 16802, USA.
Na
N
Xiong
Department of Molecular and Cell Biology, and Cancer Research Laboratory, University of California at Berkeley, Berkeley, CA 94720, USA. raulet@berkeley.edu.
David H
DH
Raulet
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D007157:Immunologic Surveillance; D007167:Immunotherapy / Q000379:methods; D007694:Killer Cells, Natural / Q000276:immunology*; D008024:Ligands; D008213:Lymphocyte Activation; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy; D008565:Membrane Proteins; D051379:Mice; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology
D002352:Carrier Proteins; D015395:Histocompatibility Antigens Class I; D008024:Ligands; D008565:Membrane Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011994:Recombinant Proteins; C468260:UL16 binding protein 1, mouse