Abstract 1070: Evaluation of human NK cell responses to PDX tumors in humanized NOD-scid IL2rgnull(NSG) mice expressing human IL15

Human innate immunity plays a critical role in tumor surveillance and in immunoregulation within the tumor microenvironment. Natural killer (NK) cells are innate lymphoid cells that have opposing roles in the tumor microenvironment, including NK cell subsets that mediate tumor cell cytotoxicity and subsets with regulatory function that contribute to the tumor immune suppressive environment. 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. 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. To enhance NK cell development, we have developed NSG mice that constitutively expresses human IL15 using a BAC containing the human IL15 gene: NSG-Tg(Hu-IL15) (NOD.Cg-Prkdcscid Il2rgtm1Wjl Tg(IL15)1Sz/SzJ; JAX stock number 030890). NSG-Tg(Hu-IL15) mice express a physiological level of human IL15 (7.1 ± 0.3 pg/ml) and support engraftment of human CD34+ hematopoietic stem cells (HSC). Following HSC-engraftment of NSG-Tg(Hu-IL15) mice, significantly higher levels of human CD56+ NK cells are detectable as compared to NSG mice in peripheral blood and within the spleen and bone marrow. Levels of circulating human CD3+ T cells, CD20+ B cells and CD33+ myeloid cells are similar between the HSC-engrafted NSG-Tg(Hu-IL15) and NSG mice. We have described that the human NK cells developing in HSC-engrafted NSG-Tg(Hu-IL15) mice are functional, mediating direct cytotoxicity and ADCC. We have now extended these observation by evaluating the ability of human NK cells to control growth of a PDX melanoma in humanized NSG-Tg(Hu-IL15) mice. Our observations indicate that the growth kinetics of the PDX melanoma are significantly delayed in HSC-engrafted NSG-Tg(Hu-IL15) mice as compared to HSC-engrafted NSG mice. Importantly PDX melanoma growth is not significantly different in NSG-Tg(Hu-IL15) and NSG that are not engrafted with human immune systems. To determine the immune cell subsets contributing to the delayed PDX growth in HSC-engrafted NSG-Tg(Hu-IL15) mice we performed experiments where either human CD8 T cells or human NK cells were depleted. Depletion of human CD8 T cells did not alter the PDX growth kinetics in HSC-engrafted NSG-Tg(Hu-IL15). In contrast, NK cell depletion abrogated the delayed growth of the PDX melanoma, suggesting that human NK cells are directly suppressing tumor growth in HSC-engrafted NSG-Tg(Hu-IL15) mice. Together these data demonstrate that HSC-engrafted NSG-Tg(Hu-IL15) mice support enhanced development of functional human NK cells and that these NK cells limit the growth of PDX tumors. Citation Format: Ken-Edwin Aryee, Lisa Burzenski, Dale L. Greiner, Giles F. Whalen, Li-Chin Yao, Leonard D. Shultz, James G. Keck, Michael A. Brehm. Evaluation of human NK cell responses to PDX tumors in humanized NOD-scid IL2rgnull (NSG) mice expressing human IL15 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1070.