Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 45, Pages E9626-E9634Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1705301114
Keywords
humanized mice; cancer immunotherapy; IL-15; NK cells; ILC
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Funding
- Erwin Schrodinger Fellowship (Austrian Science Fund) [J3220-B19]
- NIH [1K99AI125065-01, T32 AI07019, T32 AR 7107-37, AI 089992]
- short-term grant abroad (KWA) scholarship (University of Vienna)
- Austrian Marshall Plan Foundation
- Leukemia and Lymphoma Society
- Netherlands Organization of Scientific Research
- Cancer Research Institute Irvington Fellowship Program
- Bill and Melinda Gates Foundation
- Howard Hughes Medical Institute
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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 SRG15 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.
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