Herndler-Brandstetter et al. created a humanized mouse model (SRG-15) that supports the development and functional maturation of circulating and tissue-resident NK and CD8+ T cells, and the development of innate lymphoid cell subsets, by knock-in of human IL15 and human SIRPA to mice on a Rag2-/- Il2rg-/- background and engraftment of human hematopoietic stem and progenitor cells. NK cells of SRG-15 mice were able to inhibit growth of a lymphoma xenograft via ADCC, following antibody treatment.

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.

Author Info: (1) Department of Immunobiology, Yale University School of Medicine, New Haven, CT (2) Department of Immunobiology, Yale University School of Medicine, New Haven, CT (3) Department

Author Info: (1) Department of Immunobiology, Yale University School of Medicine, New Haven, CT (2) Department of Immunobiology, Yale University School of Medicine, New Haven, CT (3) Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06519. (4) Department of Immunobiology, Yale University School of Medicine, New Haven, CT (5) Department of Immunobiology, Yale University School of Medicine, New Haven, CT (6) Department of Immunobiology, Yale University School of Medicine, New Haven, CT (7) Department of Immunobiology, Yale University School of Medicine, New Haven, CT (8) Department of Immunobiology, Yale University School of Medicine, New Haven, CT (9) Department of Immunobiology, Yale University School of Medicine, New Haven, CT (10) Department of Immunobiology, Yale University School of Medicine, New Haven, CT (11) Department of Medicine, Stanford University School of Medicine, Stanford, CA (12) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591. (13) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591. (14) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591. (15) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591. (16) Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591. (17) Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06519. (18) Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519; richard.flavell@yale.edu. Howard Hughes Medical Institute, New Haven, CT 06519.