Human fused NKG2D-IL-15 protein controls xenografted human gastric cancer through the recruitment and activation of NK cells

• Published in: Cellular & molecular immunology 2017-03, Vol.14 (3), p.293-307
• Main Authors: Chen, Yan, Chen, Bei, Yang, Ti, Xiao, Weiming, Qian, Li, Ding, Yanbing, Ji, Mingchun, Ge, Xiaoqun, Gong, Weijuan
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Antigens, CD - metabolism; Antineoplastic Agents; Biomedical and Life Sciences; Biomedicine; CD56 antigen; CD8 antigen; Cell activation; Cell Line, Tumor; Cell Membrane - metabolism; Cell proliferation; Ectopic expression; Escherichia coli; Fusion protein; Gastric cancer; Histocompatibility Antigens Class I - metabolism; Humans; Immobilized Proteins - metabolism; Immunology; Immunotherapy; Interleukin 15; Interleukin 2; Interleukin-15 - metabolism; Killer Cells, Natural - immunology; Leukocytes (mononuclear); Lymphocyte Activation - immunology; Lymphocytes T; Major histocompatibility complex; Medical Microbiology; Melanoma; Mice, Nude; Microbiology; Natural killer cells; NK Cell Lectin-Like Receptor Subfamily K - metabolism; NKG2 antigen; NK细胞; Peripheral blood mononuclear cells; Protein Binding; Proteins; Recombinant Fusion Proteins - immunology; research-article; Stomach Neoplasms - immunology; Stomach Neoplasms - pathology; Tumor cells; T细胞增殖; Vaccine; Xenograft Model Antitumor Assays; Xenografts; 人类; 外周血单个核细胞; 活化性; 白细胞介素15; 胃癌细胞; 蛋白质
• ISSN: 1672-7681; 2042-0226
• DOI: 10.1038/cmi.2015.81

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 coll. 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 （B 16BL6-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-I L- 15 treatment. Human dsNKG2 D-I L- 15 also delayed the growth of transplanted melanoma （B 16BL6- 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.