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Proc Natl Acad Sci U S A. 2017 Nov 7;114(45):E9626-E9634. doi: 10.1073/pnas.1705301114. Epub 2017 Oct 25.

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

Author information

1
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519.
2
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06519.
3
Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305.
4
Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591.
5
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519; richard.flavell@yale.edu.
6
Howard Hughes Medical Institute, New Haven, CT 06519.

Abstract

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.

KEYWORDS:

IL-15; ILC; NK cells; cancer immunotherapy; humanized mice

PMID:
29078283
PMCID:
PMC5692533
DOI:
10.1073/pnas.1705301114
[Indexed for MEDLINE]
Free PMC Article

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