Abstract 5674: Transgenic expression of human IL15 in NOD-scid IL2rg
null (NSG) mice enhances the development and survival of functional human NK cells
Authors: Aryee Ken-Edwin , Burzenski Lisa , Greiner Dale L. , Welsh Raymond M. , Shultz Leonard D. , Keck James G. , Brehm Michael A. 
Published: August 2018

Abstract
The human innate immune system plays critical roles in tumor surveillance and in immunoregulation within the tumor microenvironment. Natural killer (NK) cells are innate lymphoid cells that mediate tumor cell killing by antibody-dependent cell mediated cytotoxicity (ADCC), through direct recognition, and by the expression of chimeric antigen receptors that directly target tumors. However, NK cell subsets with regulatory functionality also contribute to the tumor immune suppressive environment that enables tumor growth. The balance between effector and regulatory NK cell subsets has been studied extensively in murine models of cancer, but there is a paucity of models to study human NK cell function in tumorigenesis, which is restricted primarily to in vitro experiments. Humanized mice are a powerful alternative to syngeneic mouse tumor models for the study of human immuno-oncology and have proven effective tools to test immunotherapies targeting T cells. However human NK cell development and survival in humanized mice are severely limited. Previous studies have demonstrated that injection or transient expression of human IL15 enables efficient development of functional human NK cells within immunodeficient mice that were engrafted with CD34+ HSC. Based on these results we established NSG mice that constitutively expresses human IL15. The NSG-Tg(Hu-IL15) mice were generated using a BAC containing the human IL15 gene, and express a physiological level of human IL15 (7.1 ± 0.3 pg/ml). To evaluate human NK cell development, 8 to 12-week-old NSG and NSG-Tg(Hu-IL15) mice received 200 cGy irradiation and were then injected intravenously with 1x105 CD34+ HSC derived from umbilical cord blood. No difference in overall survival of HSC-engrafted NSG-Tg(Hu-IL15) mice compared to NSG mice were observed during the experiment, indicating that expression of IL15 did not increase mortality. Levels of circulating human CD45+ cells, T cells and B cells were similar between the HSC-engrafted NSG-Tg(Hu-IL15) and NSG mice. Significantly higher levels of human CD56+ NK cells were found in NSG-Tg(Hu-IL15) mice as compared to NSG mice at all time points tested in the peripheral blood and within the spleen and bone marrow. A higher proportion of human CD56+ NK cells recovered from the blood and spleen of NSG-Tg(Hu-IL15) mice expressed granzyme A, granzyme B and perforin as compared to NK cells from NSG mice, suggesting that the NK cells were functional. Moreover, human NK cells enriched from the NSG-Tg(Hu-IL15) mice lysed K562 cells in an in vitro cytotoxicity assay. These data demonstrate that HSC-engrafted NSG mice expressing human IL15 support enhanced development of functional human NK cells and suggest that HSC-engrafted NSG-Tg(Hu-IL15) mice are a powerful model to study the role of NK cells in tumor-immune system interactions and to test immunotherapies targeting NK cells.
Citation Format: Ken-Edwin Aryee, Lisa Burzenski, Dale L. Greiner, Raymond M. Welsh, Leonard D. Shultz, James G. Keck, Michael A. Brehm. Transgenic expression of human IL15 in NOD-scid IL2rgnull (NSG) mice enhances the development and survival of functional human NK cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5674.