Joint Fellowship Training Program
Mentor:
Francisco Borrego M.D., Ph.D.
Organizational Affiliation and Position:
Principal Investigator,
Laboratory of Molecular and Developmental Immunology, Division of Monoclonal Antibodies, OBP, CDER, FDA.
Email:
Francisco.Borrego@fda.hhs.gov
Telephone:
301-827-0809
Running Title of Program:
Mechanisms of priming human natural killer (NK) cells for defense against cancer.
Research Project Summary:
Natural killer (NK) cells are a major component of the innate immune system and they serve as the first line of defense against malignant transformation and viral infections. To accomplish this, NK cells are primed by dendritic cells (DC) and they secrete cytokines, such as interferon (IFN)-γ and tumor necrosis factor (TNF)-α, that have anti-tumor activity. Primed NK cells are able to recognize and kill cancer cells by mechanisms that involve the release of cytotoxic granules along with additional IFN-γ and TNF-α secretion. NK cell activity is controlled by the balance of inhibitory and activating signals. The inhibitory signals represent potential targets to effectively enhance NK cell cytotoxicity against tumors.
We are studying the mechanisms that DC use to effectively prime NK cells in the defense against cancer and viral infections. Both pro- and anti-inflammatory cytokines produced by DC regulate the IFN-γ and TNF-α production by NK cells and the enhancement of their cytotoxic capacity. The interaction of different signaling pathways is very important to provide an integrated response to the NK cell total signal input. These signals will ultimately impact the levels of transcription factors that control the expression of genes during the priming and activation of NK cells. What transcription factors are involved and how these transcription factors control the expression of NK cell specific genes is not very well known. Our preliminary results suggest that, in addition to the known transcription factors, such as T-bet, that are important for NK cell function, other transcription factors may be involved in priming human NK cells, such as eomesodermin (Eomes) and Runx3. It is our goal to delineate the role of these transcription factors and how they interact between each other. The acquired knowledge will eventually be used to formulate cancer therapies by targeting NK cell functions.
Proposed Project for IOTF Fellow:
The fellow will investigate the molecular mechanisms accountable for the priming of human NK cells obtained from peripheral blood. To carry out this research he/she will generate a battery of reagents necessary to study the transcription factors that are involved in the expression of NK cell specific genes. These transcription factors include, among others, T-bet, Eomes and Runx3. The fellow will make lentiviral constructs to over-express and knock down these transcription factors and will develop a successful strategy to transduce human NK cells.
The role of the transcription factors will be studied with two functional assays: first, IFN-γ and other cytokines, such as TNF-α, production by NK cells in response to DC signals and second, cytotoxic assays against cancer cell lines of different origins.
We are looking for a creative, energetic and self-motivated scientist that will help us to develop a research program dedicated to advancing the FDA and NCI cooperative effort to develop better therapies for people living with cancer.
Regulatory Activity:
The Division of Monoclonal Antibodies is responsible for product review of antibodies, antibody conjugates, Fab's, ScFv, Ig-linked fusion proteins, and other antibody related proteins, including those currently under development for detection and treatment of cancer. The fellow will be mentored to enable participation in regulatory efforts such as pre-IND and IND guidance. This entails evaluation of manufacturing and controls, as well as product characterization including mechanism of action, to assure the availability of safe, effective and consistent products.
