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Metabolic control of immune cell fate by hypoxia-inducible factors 10.17863/CAM.64167 Bargiela, David Johnson, Randall 0000000240846639 Oxygen 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. University of Cambridge 2020-09-15 Thesis Doctoral Doctor of Philosophy (PhD) eng Wellcome Trust PhD for Clinicians Fellowship https://www.repository.cam.ac.uk/handle/1810/317056 controlled.access https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/ae855fef-47a5-4169-9b8d-96699857a5d1/download 98735cb138cbb7e19eb70053a7e2d675 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/bf262c1d-3776-4add-95b4-b7b3993a80eb/download 353adac0d1ebdfd65ab16480263c3c87 https://www.rioxx.net/licenses/all-rights-reserved/ oxygen HIF metabolism