National Institutes of Health (NIH)
Funding Opportunity Title
Enhancing Tumoricidal Activity of Natural Killer (NK) Cells by Dietary Components for Cancer Prevention (R21)
R21 Exploratory/Developmental Research Grant Award
Reissue of PA-08-132
Funding Opportunity Announcement (FOA) Number
Catalog of Federal Domestics Assistance (CFDA) Number(s)
93.393, 93.396, 93.213
This funding opportunity announcement (FOA) is designed to stimulate research efforts aimed at establishing the physiological significance of dietary components in modulating the tumoricidal cell activity of natural killer (NK) cells for cancer prevention.
March 17, 2011
Open Date (Earliest Submission Date)
May 16, 2011
Letter of Intent Due Date
Application Due Date(s)
Standard dates apply, by 5:00 PM local time of applicant organization.
AIDS Application Due Date(s)
Standard dates apply, by 5:00 PM local time of applicant organization.
Scientific Merit Review
Standard dates apply
Advisory Council Review
Standard dates apply
Earliest Start Date(s)
Standard dates apply
May 8, 2014
Due Dates for E.O. 12372
Required Application Instructions
It is critical that applicants follow the instructions in the SF 424 (R&R) Application Guide except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.
Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information
This NCI-sponsored Funding Opportunity Announcement (FOA)
promotes research to characterize the significance of dietary components in
regulating the tumoricidal activity of natural killer (NK) cells for cancer
prevention. Specifically, this FOA encourages studies that can establish the
physiological significance of dietary components in modulating the tumoricidal
activity of NK cells. Research projects that are appropriate to this FOA should
focus on defining the minimum quantity and duration of exposure to specific
dietary components to modulate tumoricidal activity of NK cells for cancer
prevention and the underlying mechanism(s) accounting for this response.
Appropriate research projects are encouraged to include animal and/or human investigations. . In vitro models can be used only to support in vivo studies, and therefore, should not constitute the primary focus of the application. Molecular targets for food components may be examined at the sites of: 1) the tumoricidal cell receptors and cancer cell specific ligands; 2) the release of tumoricidal cytokines such as IFN-gamma; and 3) the release of lytic granules such as granulysin, perforin, and serine proteases (granzymes).
Related Funding Opportunity: Investigators, who are interested in proposing exploratory and developmental research projects, should submit applications in response to the partner FOA of identical scientific scope (PA-11-160), which uses the NIH Research Project Grant (R01) funding mechanism.
The growth and spread of cancer depend not only on the
biological characteristics of the tumor per se but also on the host responses.
NK cells represent one significant venue for influencing tumor growth and
metastasis. NK cells are large granular lymphocytes without B or T cell
characteristics; these cells are highly effective killers of both tumor cells
and virally infected cells without the need for prior sensitization or
recognition of a specific antigen. An important characteristic of cancer is
that the disease can overcome the surveillance of the immune system. One
possible explanation for this resistance (to immune surveillance) arises from
the ability of tumor cells to inactivate the tumoricidal activity of hosts NK
cells, thereby evading this first-line immune defense mechanism. Furthermore,
inappropriate changes in microenvironment caused by treatment with various
drugs, such as interferons (IFNs), and Interleukin-2 (IL-2) that can
up-regulate NK cell activity, result in their attacking both self and non-self
cells. Thus, it is extremely important to understand the early stage(s) of
tumor-host interactions, and redirect these events from a pro-tumor to an
anti-tumor state. Diet may represent a subtle approach to regulating NK cells
without losing their self-tolerance mechanism.
Several lines of preliminary evidence suggest that a number of bioactive food components can induce tumor cell death, possibly by enhancing NK cell activity. For example, extracts of the Maitake- (Grifola frondosa) and Brazilian sun- mushrooms (Agaricus Blazei) can enhance the cytolytic activity of NK cells in tumor-bearing mice. Likewise, dietary supplementation with 250 mg vitamin E/day (for 2 weeks) can enhance NK cell cytolytic activity in advanced colorectal cancer patients. In addition, the supplementation of vitamin E (administered at 100 mg/day for 8 weeks) restored NK cell activity in a 16 month-old boy with Shwachman-Diamond syndrome that is classically associated with a persistent reduction in NK cytolytic activity. However, these preliminary findings and rare cases are only suggestive of the involvement of dietary components in regulation of the tumoricidal activity of NK cells. The precise role(s) by which these and other dietary components influence NK cells, such as modulation of receptor-ligand interactions and/or the release of cytokines and lytic enzymes, remains largely unknown.
Both experimental and clinical data indicate an important role for NK cells in early neoplastic development, possibly by either responding to specific ligands generated by cancer cells, or to various types of extracellular or cell-associated proteinases. NK cells are known to exert their activity through a diverse repertoire of activating (e.g., NKG2 receptor family) and inhibitory (e.g., killer immunoglobulin-like receptor [KIR] family) receptors that recognize specific ligands on the surface of target cells. Many of the KIRs recognize major histocompatibility (MHC) class I molecules, which in humans are human leukocyte antigen (HLA) class I molecules. The KIRs provide protection for cells that express normal levels of MHC class1 molecules on their surface. In general, the co-ligation of activating and inhibitory receptors results in a net negative (i.e., no cytotoxicity) reaction. In contrast, the down-regulation of MHC class I in cancer, together with expression of specific ligands for activating receptors such as MICA, MICB, or UL16-binding proteins, enhances the sensitivity of target cells to NK cell-mediated cytotoxicity.
There is some evidence to suggest that certain dietary
components may modulate the NK cell activity in response to antigen stimuli.
For example, when C57BL/6J mice were maintained for eight weeks on Selenium
(Se)-deficient (~0.02 ppm), Se-normal (~0.20 ppm), or Se-supplemented (~2.00
ppm) diets, lymphocyte activity was differentially modulated; lymphocytes
isolated from animals maintained on the Se-supplemented diets had an enhanced
ability to destroy tumor cells compared with lymphocytes from animals that were
maintained on either a normal or Se-deficient diet. While these studies support
the general concept that specific dietary components can modify tumoricidal
activity of NK cells, the evidence largely remains indirect. Therefore, the
underlying mechanisms deserve additional study in order to develop and optimize
future intervention strategies.
Circulating NK cells are mature, as opposed to dendritic cells, which only mature during inflammation or infection. During early onset inflammation, immature dendritic cells secrete a variety of cytokines including tumor necrosis factor alpha (TNF-alpha), IL-2, and IL-12. These cytokines can induce a rapid expression of IFN-gamma and subsequently enhance the intrinsic cytolytic activity of NK cells. However, the response is complex since a T-Helper 2 (TH2) cytokine such as IL-4, which is generally viewed as an antagonist of IFN-gamma expression (in T cells), can induce signal transducer and activator of transcription 6 (STAT6)-dependent IFN-gamma secretion by NK cells. While some evidence suggests that specific bioactive food components (such as those derived from fermentable fibers and mushrooms) can modulate the release of various cytokines, it remains unclear whether these changes accompany a proportional alteration in the NK cell activity. NK cells, which can lyse tumor cells, provide antigenic cellular debris for mature dendritic cells to present to T cells; in later stages, NK cells terminate the process by lysing the dendritic cells and halting their ability for antigen presentation.
The lysosomal release of cytotoxic granules from NK cells, including two membrane-perturbing proteins such as perforin and granulysin, and a family of serine proteases (also known as granzymes), constitutes the main pathway for the immune system-mediated elimination of tumor cells. A number of studies indicate that dietary habits, including caloric restriction and alcohol consumption, may influence the cytolytic activity of NK cells by down-regulating the release, activity, and expression of perforin and granular proteases. Nevertheless, these observations need to be further characterized in mechanistic studies to establish a link between dietary modulation and cancer prevention.
NK cells, once activated, initiate the tumoricidal process through the release of both lytic granules and serine proteases (granzymes) or tumor-suppressive cytokines such as IFN-gamma, to mediate transformed cell death. Support for these findings comes from the inability of cytotoxic T lymphocytes (CTLs) to kill their target cells in either perforin-null or ashen mice that possess impaired granule pathway. Recently, genetically modified mouse cancer models have been extensively used for analyzing the occurrence of molecular events during the tumoricidal process. Analogous studies have also been conducted in humans with diseases caused by defects in tumor cell killing. Since a number of dietary components may influence NK cell tumoricidal activity, it would be prudent to use various models to establish the physiological significance of dietary components as either cancer protectants or modulators of cancer risk.
An example of the usefulness of the defined mouse model systems comes from studies using a recombination activating gene 2-deficient (RAG-2 -/-) mice. These mice fail to produce mature lymphocytes, which are critical for generating active forms of perforin and IFN-gamma. Consequently, RAG-2 -/- mice are highly susceptible to spontaneous development of adenocarcinomas in colon and lungs. Tumor growth in these genetically engineered mice was shown to be suppressed in response to dietary supplementation with Brazilian sun-mushrooms (Agaricus Blazei). A. blazei is an edible mushroom with anticancer activity native to Brazil; oral intake of A. blazei can enhance NK cell activation through IL-12-mediated IFN-gamma production.
Another mouse model includes deficiencies in STAT1 gene that is critical for the function of IFN-gamma. Double knockout animals of STAT1 -/- and RAG-2 -/- not only exhibit early onset of malignancy in colon and lung, but also demonstrate an exaggerated incidence of mammary cancers. In addition, mice with deficiencies in a subunit of IFN receptor expression (IFNAR -/-) were successfully used to demonstrate that endogenous Type 1 IFN is critical for controlling NK cell-mediated anti-tumor responses. These findings suggest that both IFN-gamma and perforin are critical in regulating some solid tumors. Therefore, the use of these models for determining the influence of bioactive food components on NK cell activity warrants further studies, given the literature evidence that several food items can modulate cancer risk, especially in cancers of the colon, lung, prostate, and mammary tissue.
The goal of this FOA is to encourage studies that can establish the physiological significance of dietary components in modulating the tumoricidal activity of NK cells for cancer prevention. The focus of the research should be on defining the minimum quantity and duration of exposure to specific dietary components to modulate tumoricidal activity of NK cells for cancer prevention and the underlying mechanism(s) accounting for this response. Both animal- and human- based investigations are appropriate to this FOA. Highly purified populations of immune cells, specific tumor cell lines, target cell-free systems, or single-cell assays may be used to define the molecular bases for diet-induced changes in NK tumoricidal activity. However, in vitro information can be used only to support in vivo studies, and therefore, should not constitute the primary focus of the application. Molecular targets for food components may be examined at the sites of: 1) the tumoricidal cell receptors and cancer cell specific ligands; 2) the release of tumoricidal cytokines such as IFN-gamma; and 3) the release of lytic granules such as granulysin, perforin, and serine proteases (granzymes).
A variety of technologies including those of genomics, proteomics, and metabolomics can be used to identify and characterize the molecular targets for dietary components, as well as the methods for monitoring tumoricidal activity of NK cells, which correlate with cancer prevention. The use of transgenic and/or conditional knockout mouse models that are associated with alterations in NK cell tumoricidal function is encouraged; several of these mouse models are available through the Mouse Models for Human Cancer Consortium (MMHCC). The efficient utilization of molecular resources such as gene, protein, and metabolome databases may be used to expedite the proposed research studies. Bioinformatics-based approaches may also be necessary to identify the complex patterns of alterations in genes, proteins, and metabolites, which can generate unique fingerprints for any given dietary treatments. Applicants are encouraged to use research information resources available at the NCI Center for Bioinformatics (NCICB).
NCCAM’s research interests relevant to this FOA include, but are not limited to, the following examples:
Natural products research supported by the National Center for Complementary and Alternative Medicine must comply with NCCAM’s Natural Product Integrity policy.
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