This proposal is now in its fourth cycle of competitive funding and focuses on Interleukin 15 (IL-15) and its role in human natural killer (NK) cell development, NK cell effector function and cancer.
Our specific aims remain relatively unchanged: 1) To further identify and characterize progenitors and precursors that differentiate into human NK cells; 2) To better understand the role of IL-15 in regulating human NK cell effector functions. IL-15 induced differentiation and activation of NK cells are, like other biologc systems balanced by negative regulators, and those negative regulators are in turn exploited by tumors to turn off and evade the NK cell's ability to effectively survey against malignant transformation. Thus, our overall goal in this proposal is to gain a comprehensive understanding of the cellular and molecular components that constitute these inhibitory pathways in order to best understand how they work and how they can be modified to enhance NK cell development and function in the face of tumor challenge. In particular, in Aim 1 we will further investigate th innate cellular heterogeneity within secondary lymphoid tissues where we previously discovered and characterized human NK cell developmental intermediates. Over the past five years, an abundance of additional innate lymphoid cells (ILC) have been discovered and characterized, lending some controversy as to the origin of human NK cells. We hypothesize that the transcription factor aryl hydrocarbon receptor (AHR) acts to prevent human NK cell development from an IL-22 secreting ILC, and does so via the upregulation of miR-29b. Indeed, certain tumors have been shown to secrete AHR agonists that we postulate inhibit NK cell development. We propose a series of experiments to test our hypothesis, which if validated, will provide a new target for combating immune evasion.
In Aim 2 we have preliminary data that suggest the activated Axl/Mer/Tyro3 receptor tyrosine kinase (RTK) pathway serves to negatively regulate IL-15-induced NK cell activation. Further, we have shown that the ligand to this RTK family, Gas6, is expressed on human acute myeloid leukemia cells and confers a poor prognosis. Thus, we hypothesize that this family of RTKs plays an important role in the negative regulation of NK cell effector functions and thus has the potential to be targeted for immune checkpoint inhibition in order to enhance NK cell-mediated immune therapy against cancer.

Public Health Relevance

Cancer is now the leading cause of death in individuals infected with the human immunodeficiency virus, reminding us how important a competent immune system is for cancer prevention. The recent successful development of the vaccine preventing human papilloma virus infection illustrates the power and rewards of immunology research. Funding of this proposal will advance our understanding of basic immunology as well as strategies to prevent and treat cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA068458-24
Application #
9849964
Study Section
Transplantation, Tolerance, and Tumor Immunology Study Section (TTT)
Program Officer
Howcroft, Thomas K
Project Start
1996-07-01
Project End
2020-03-31
Budget Start
2019-01-14
Budget End
2019-03-31
Support Year
24
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Beckman Research Institute/City of Hope
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
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Victor, Aaron R; Weigel, Christoph; Scoville, Steven D et al. (2018) Epigenetic and Posttranscriptional Regulation of CD16 Expression during Human NK Cell Development. J Immunol 200:565-572
Deng, Youcai; Wang, Fangjie; Hughes, Tiffany et al. (2018) FOXOs in cancer immunity: Knowns and unknowns. Semin Cancer Biol 50:53-64
Scoville, Steven D; Nalin, Ansel P; Chen, Luxi et al. (2018) Human AML activates the aryl hydrocarbon receptor pathway to impair NK cell development and function. Blood 132:1792-1804
Chan, Wing Keung; Kang, Siwen; Youssef, Youssef et al. (2018) A CS1-NKG2D Bispecific Antibody Collectively Activates Cytolytic Immune Cells against Multiple Myeloma. Cancer Immunol Res 6:776-787
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Wang, Yufeng; Zhang, Yibo; Hughes, Tiffany et al. (2018) Fratricide of NK Cells in Daratumumab Therapy for Multiple Myeloma Overcome by Ex Vivo-Expanded Autologous NK Cells. Clin Cancer Res 24:4006-4017
Zhang, Xinfu; Zhang, Chengxiang; Yang, Xiaomei et al. (2018) Design, synthesis and evaluation of anti-CD38 antibody drug conjugate based on Daratumumab and maytansinoid. Bioorg Med Chem :
Freud, Aharon G; Mundy-Bosse, Bethany L; Yu, Jianhua et al. (2017) The Broad Spectrum of Human Natural Killer Cell Diversity. Immunity 47:820-833
Chen, L; Mao, H; Zhang, J et al. (2017) Targeting FLT3 by chimeric antigen receptor T cells for the treatment of acute myeloid leukemia. Leukemia 31:1830-1834

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