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dc.contributor.authorBargiela, Daviden
dc.description.abstractOxygen is required for life and is a major determinant of mammalian cell fate. Vital systems are driven by the activity of oxygen-dependent enzymes within fundamental processes, such as cellular metabolism and gene transcription. The hypoxia-inducible factors (HIFs), which are regulated by oxygen-sensing hydroxylases, have a central role in maintaining oxygen homeostasis in cells throughout the body. This work explores the role of HIF signalling in T cells and how modulation of this signalling may be harnessed to potentiate the immune response against cancer. The thesis is divided in two parts, each considering a key aspect of HIF activity: i) the metabolic consequence of transcriptional activity downstream of HIF and ii) the metabolic control of the regulators lying upstream of HIF. Chapter 2 describes the discovery of HIF1-dependent modulation of vitamin B6 metabolism via pyridoxal phosphate phosphatase (PDXP), and the effect of pharmacological targeting of vitamin B6-dependent enzymes in primary and malignant T cells. Vitamin B6-dependent enzymes are shown to be essential for the proliferation and effector differentiation of T cells in vitro and required to support T cell expansion and effective anti-tumour responses in vivo in mice. These findings highlight HIF1-dependent vitamin B6 metabolism as a key modulator of T cell fate and a promising potential target to improve cancer immunotherapy. In Chapter 3, the role of factor inhibiting HIF (FIH) in directing T cell metabolism and fate is explored. Using a mouse T cell-specific FIH knockout model, FIH is shown to regulate T cell differentiation in an oxygen-dependent manner. Furthermore, by considering a metabolic network of related enzymes that compete for the same cosubstrates, FIH activity is predicted, and demonstrated, to be optimal under conditions where oxygen levels are non-limiting and HIF levels are maximised. The therapeutic benefit of targeting FIH to limit in vivo tumour growth in mice is evaluated by deleting FIH in both T cell and tumour cell compartments. Taken together, these findings describe a dynamic metabolic feedback loop in which HIF activity modulates pathways that are critical to T cell proliferation and differentiation, and in turn is regulated by metabolic competition between HIF hydroxylases and other cell fate-determining hydroxylases. This interdependence allows for amplification of targeted metabolic alterations via downstream transcriptional responses as a strategy to improve anti-tumour T cells function.en
dc.description.sponsorshipWellcome Trust PhD for Clinicians Fellowshipen
dc.rightsAll rights reserveden
dc.rightsAll rights reserveden
dc.rightsAll rights reserveden
dc.rightsAll rights reserveden
dc.rightsAll rights reserveden
dc.titleMetabolic control of immune cell fate by hypoxia-inducible factorsen
dc.publisher.institutionUniversity of Cambridgeen
pubs.funder-project-idWellcome Trust (204017/Z/16/Z)
cam.supervisorJohnson, Randall

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