title: Human fused NKG2D-IL-15 protein controls xenografted human gastric cancer through the recruitment and activation of NK cells.
abstract: Interleukin (IL)-15 plays an important role in natural killer (NK) and CD8+ T-cell proliferation and function and is more effective than IL-2 for tumor immunotherapy. The trans-presentation of IL-15 by neighboring cells is more effective for NK cell activation than its soluble IL-15. In this study, the fusion protein dsNKG2D-IL-15, which consisted of two identical extracellular domains of human NKG2D coupled to human IL-15 via a linker, was engineered in Escherichia coli. DsNKG2D-IL-15 could efficiently bind to major histocompatibility complex class I chain-related protein A (MICA) of human tumor cells with the two NKG2D domains and trans-present IL-15 to NK or CD8+ T cells. We transplanted human gastric cancer (SGC-7901) cells into nude mice and mouse melanoma cells with ectopic expression of MICA (B16BL6-MICA) into C57BL/6 mice. Then, we studied the anti-tumor effects mediated by dsNKG2D-IL-15 in the two xenografted tumor models. Human dsNKG2D-IL-15 exhibited higher efficiency than IL-15 in suppressing gastric cancer growth. Exogenous human dsNKG2D-IL-15 was centrally distributed in the mouse tumor tissues based on in vivo live imaging. The frequencies of human CD56+ cells infiltrated into the tumor tissues following the injection of peripheral blood mononuclear cells into nude mice bearing human gastric cancer were significantly increased by human dsNKG2D-IL-15 treatment. Human dsNKG2D-IL-15 also delayed the growth of transplanted melanoma (B16BL6-MICA) by activating and recruiting mouse NK and CD8+ T cells. The anti-melanoma effect of human dsNKG2D-IL-15 in C57BL/6 mice was mostly decreased by the in vivo depletion of mouse NK cells. These data highlight the potential use of human dsNKG2D-IL-15 for tumor therapy.Cellular & Molecular Immunology advance online publication, 14 September 2015; doi:10.1038/cmi.2015.81.
authors.affiliation: Department of Immunology, School of Medicine, Yangzhou University, Yangzhou 225001, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, School of Medicine, Yangzhou University, Yangzhou 225001, People's Republic of China.
authors.forename: Bei
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Immunology, School of Medicine, Yangzhou University, Yangzhou 225001, People's Republic of China.
authors.forename: Ti
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of Gastroenterology, The Second Affiliated Hospital, Yangzhou University, Yangzhou 225001, People's Republic of China.
authors.forename: Weiming
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Department of Immunology, School of Medicine, Yangzhou University, Yangzhou 225001, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Qian
authors.affiliation: Department of Gastroenterology, The Second Affiliated Hospital, Yangzhou University, Yangzhou 225001, People's Republic of China.
authors.forename: Yanbing
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Immunology, School of Medicine, Yangzhou University, Yangzhou 225001, People's Republic of China.
authors.forename: Mingchun
authors.initials: M
authors.lastname: Ji
authors.affiliation: Department of Pharmacology, School of Medicine, Yangzhou University, Yangzhou 225001, People's Republic of China.
authors.forename: Xiaoqun
authors.initials: X
authors.lastname: Ge
authors.affiliation: Department of Immunology, School of Medicine, Yangzhou University, Yangzhou 225001, People's Republic of China.|Department of Gastroenterology, The Second Affiliated Hospital, Yangzhou University, Yangzhou 225001, People's Republic of China.|Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou 225009, People's Republic of China.|Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou 225009, People's Republic of China.|Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, People's Republic of China.
authors.forename: Weijuan
authors.initials: W
authors.lastname: Gong
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000970:Antineoplastic Agents; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D055767:Immobilized Proteins / Q000378:metabolism; D019409:Interleukin-15 / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008819:Mice, Nude; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000276:immunology*; D013274:Stomach Neoplasms / Q000276:immunology* / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; D015395:Histocompatibility Antigens Class I; C569274:IL15 protein, human; D055767:Immobilized Proteins; D019409:Interleukin-15; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011993:Recombinant Fusion Proteins