The role of metabolism in the anti-tumor cytotoxicity of natural killer cells
Lewis, Derrick Brian
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Since their discovery, natural killer cells (NK) cells have been implicated as important players in cancer immunosurveillance. In recent years, researchers have taken advantage of this role by developing NK cell-based immunotherapies in the fight against cancer. While these treatments have been moderately successful against hematological malignancy, they are less effective against solid cancers. This lack of success partially results from the immunosuppressive effects of the tumor microenvironment (TME). While tumors use myriad processes to evade the immune system, the avid consumption of nutrients common to NK and cancer cell metabolism and the production of toxic waste products can have significant deleterious effects on NK cell anti-tumor function. However, it may be possible to avoid some of this tumor-induced inhibition of NK cell anti-tumor function by manipulating NK cell metabolism and/or environmental conditions. Recent studies have revealed that different activation regimens can affect the metabolic dependencies of different NK cell subsets. Furthermore, studies have identified potential targets in the TME that can make the environment less hostile for infiltrating NK cells. By considering the interrelationship of NK cell metabolism and function—especially in the TME—this thesis illuminates potential strategies to modulate immunometabolic suppression. Despite the promising work already done, many gaps in the knowledge of NK cell metabolism remain. Future work will need to investigate the specific molecular mechanisms linking metabolism and function, the role of tissue-resident NK cells in cancer immunosurveillance, and the influences of chronic disease and altered systemic metabolism on NK cell anti-tumor activity.
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