Natural killer cells are generally viewed as a first line of defense in cancer immunosurveillance and are critical players in immune-mediated cancer rejection. We have recently described a new subset of unconventional NK cells that reside in mucosal tissues and are characterized by production of large amounts of IL-22. We refer to this novel cell subset as NK-22. Although the origin of these cells is still unclear and their relationship to conventional NK cells a matter of debate, we and others have shown that these cells can acquire features typical of conventional NK cells when exposed to inflammatory cytokines. Moreover, recent work has suggested that a similar cell type plays a critical role in initiating tumor rejection. Our preliminary data show that NK-22 are highly dependent on the transcription factor aryl hydrocarbon receptor (AHR) for their development. AHR is known to bind dietary compounds such as indol-3-carbinol (I3C) and flavonoids that are associated with anti-tumor activity. We hypothesize that by engaging AHR through dietary supplements, we can manipulate the numbers and or the activity of NK-22.
In Specific Aim 1 we will test the effect of I3C and the flavonoid quercetin on NK-22 expansion and function in vivo.
In Specific Aim 2 we will determine whether these supplements impact the anti-tumor function of NK-22 in spontaneous and transplantable tumor models. We discovered NK-22, contributed to the initial characterization of their development and function and have generated unique NK-22 specific reagents as well as mouse strains lacking NK-22 or AHR in several immune and non-immune cell types. Therefore, we are in a unique position to directly test the impact of specific dietary supplements allegedly associated with anti-cancer activity on tumor surveillance by innate immune cells. !

Public Health Relevance

Natural Killer (NK) cells are white blood cells that play an important role in our immune defense against cancer. It is well documented that a diet rich in vegetables and fruits can provide protection from cancer. This activity has been attributed to compounds such as flavonoids and polyphenols. Some of these naturally occurring compounds bind to a transcription factor that is a master regulator of a subset of NK cells that we recently described. In this application we propose studies to explore the possibility that we can exploit dietary supplements to promote the anti-tumor activity of this NK cell subset.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA167192-01A1
Application #
8445901
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Kim, Young S
Project Start
2013-01-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
1
Fiscal Year
2013
Total Cost
$165,300
Indirect Cost
$56,550
Name
Washington University
Department
Pathology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Diefenbach, Andreas; Colonna, Marco; Koyasu, Shigeo (2014) Development, differentiation, and diversity of innate lymphoid cells. Immunity 41:354-65
Cortez, Victor S; Cervantes-Barragan, Luisa; Song, Christina et al. (2014) CRTAM controls residency of gut CD4+CD8+ T cells in the steady state and maintenance of gut CD4+ Th17 during parasitic infection. J Exp Med 211:623-33