Humanized mouse model supports development, function, and tissue residency of human natural killer cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 45; pp. E9626 - E9634
• Main Authors: Herndler-Brandstetter, Dietmar, Shan, Liang, Yao, Yi, Stecher, Carmen, Plajer, Valerie, Lietzenmayer, Melanie, Strowig, Till, de Zoete, Marcel R., Palm, Noah W., Chen, Jie, Blish, Catherine A., Frleta, Davor, Gurer, Cagan, Macdonald, Lynn E., Murphy, Andrew J., Yancopoulos, George D., Montgomery, Ruth R., Flavell, Richard A.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 07.11.2017
• Series: PNAS Plus
• Subjects: Antitumor activity; Biological Sciences; Burkitt's lymphoma; Cancer; Cancer immunotherapy; CD8 antigen; Cells (biology); Cytokines; Cytometry; Diabetes mellitus; Hematopoietic stem cells; Human behavior; Immune response; Immune system; Immunodeficiency; Immunotherapy; In vivo methods and tests; Interleukin 1; Interleukin 15; Interleukins; Lymphocytes; Lymphocytes T; Lymphoma; Monoclonal antibodies; Natural killer cells; PNAS Plus; Progenitor cells; RAG2 protein; Receptors; Rituximab; Rodents; Subpopulations; Targeted cancer therapy; Therapy; Tissues; Transplantation; Xenografts; ILC; IL-15; NK cells; cancer immunotherapy; humanized mice
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1705301114

Immunodeficient mice reconstituted with a human immune system represent a promising tool for translational research as they may allow modeling and therapy of human diseases in vivo. However, insufficient development and function of human natural killer (NK) cells and T cell subsets limit the applicability of humanized mice for studying cancer biology and therapy. Here, we describe a human interleukin 15 (IL15) and human signal regulatory protein alpha (SIRPA) knock-in mouse on a Rag2 −/− Il2rg −/− background (SRG-15). Transplantation of human hematopoietic stem and progenitor cells into SRG-15 mice dramatically improved the development and functional maturation of circulating and tissue-resident human NK and CD8⁺ T cells and promoted the development of tissue-resident innate lymphoid cell (ILC) subsets. Profiling of human NK cell subsets by mass cytometry revealed a highly similar expression pattern of killer inhibitory receptors and other candidate molecules in NK cell subpopulations between SRG-15 mice and humans. In contrast to nonobese diabetic severe combined immunodeficient Il2rg −/− (NSG) mice, human NK cells in SRG-15 mice did not require preactivation but infiltrated a Burkitt’s lymphoma xenograft and efficiently inhibited tumor growth following treatment with the therapeutic antibody rituximab. Our humanized mouse model may thus be useful for preclinical testing of novel human NK cell-targeted and combinatory cancer immunotherapies and for studying how they elicit human antitumor immune responses in vivo.