Studying the inhibitory effect of oxysterols on NK-92 metabolism and cytotoxicity

dc.contributor.advisorFinlay, David K
dc.contributor.authorAlharbi, Mona Shujaa
dc.date.accessioned2023-12-07T07:30:19Z
dc.date.available2023-12-07T07:30:19Z
dc.date.issued2023-12-05
dc.descriptionThis study is designed to investigate the metabolism and function of NK-92 cell lines. Our aim is to pinpoint the metabolic key regulators that sustain the cells' effective killing mechanism against tumour cells, utilizing inhibitors targeting factors such as mTORC1, Srebp, and cMyc. Additionally, we plan to explore the potential mechanism behind the oxysterol-mediated inhibition of NK-92 cells. The ultimate goal is to comprehend the metabolic requirements of NK-92 cells and subsequently target various metabolic and signaling pathways to enhance their resistance in the harsh tumour microenvironment (TME).
dc.description.abstractNK cell-based immunotherapy has become a promising cancer treatment for cancer. One approach is the use of NK cell lines such as NK-92 as this overcomes many of the technical challenges associated with the use of human NK cells isolated from the blood. One of the major restrictions for the activity of NK cells against solid tumours are the conditions within the tumour microenvironment (TME) including adverse metabolic conditions. The Finlay lab has discovered that cellular metabolism is closely linked to NK cell anti-tumour functions, including NK cell cytotoxicity. However, little is known about the metabolic requirements for NK-92 to mediate anti-tumour cytotoxicity. This study investigated the metabolism of NK-92 cells and the importance for metabolic regulators, including mTORC1 and SREBP, in sustaining NK-92 cytotoxicity. Direct inhibition of metabolic pathways inhibited NK-92 cytotoxicity. While IL-2 signaling is required for NK92 cytotoxicity, the activity of the downstream signaling through mTORC1 and Srebp is dispensable. Interestingly, the oxidized cholesterol molecule 25-hydroxycholesterol (25-HC), a known inhibitor of SREBP activation, potentially inhibited NK-92 cytotoxicity, mitochondrial metabolism, along with observed distribution in membrane structure, seemed to occur independently of SREBP and LXR activation. 25-HC can be made by tumour associated macrophages (TAMs) that express cholesterol-25-hydroxylase. These data argue that 25-HC in the TME would inhibit NK-92 anti-tumour activity through modifying the membrane lipid order. Understanding NK92 cell metabolism will support designing better cell-based cancer therapeutic strategies in future. The data emerging from this project suggest that one strategy would be to engineer NK-92 cells to be resistant to the actions of 25-HC.
dc.format.extent221
dc.identifier.urihttps://hdl.handle.net/20.500.14154/70103
dc.language.isoen
dc.publisherSaudi Digital Library
dc.subjectNatural Killer Cell
dc.subject25-hydroxycholesterol
dc.subject27-hydroxycholesterol
dc.subjectSterol regulatory element binding protein
dc.subjectmTORC1
dc.subjectInterleukin-2
dc.subjectNK-92 cell line
dc.subjectLXR
dc.subjectTME
dc.subjectimmunometabolism
dc.subjectNK-cancer based immunotherapy
dc.titleStudying the inhibitory effect of oxysterols on NK-92 metabolism and cytotoxicity
dc.typeThesis
sdl.degree.departmentBiochemistry and Immunology
sdl.degree.disciplineImmunometabolism
sdl.degree.grantorTrinity College Dublin
sdl.degree.nameDoctor of Philosoghy

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