{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/317056"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/317056","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"Metabolic control of immune cell fate by hypoxia-inducible factors","abstract":"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.","abstract_html":"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.","abstract_has_math":false,"creators":["Bargiela, David"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Johnson, Randall"],"committee_chairs":[],"committee_members":[],"year":2020,"date_issued":"2020-09-15","date_published":"2020-09-15","updated_at":"2026-07-22T22:24:11Z","subjects":["oxygen","HIF","metabolism"],"languages":["eng"],"rights":[],"rights_urls":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/bf262c1d-3776-4add-95b4-b7b3993a80eb/download","https://www.rioxx.net/licenses/all-rights-reserved/"],"identifier_entries":[{"key":"dc:creator.authoridentifier","label":"Author Identifier","values":["0000000240846639"],"render_values":[{"text":"0000-0002-4084-6639","href":"https://orcid.org/0000-0002-4084-6639","code":true}]}]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.64167","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Johnson, Randall"]},{"key":"dc:contributor.sponsor","label":"Sponsor","values":["Wellcome Trust PhD for Clinicians Fellowship"]},{"key":"dc:creator","label":"Author","values":["Bargiela, David"]},{"key":"dc:creator.authoridentifier","label":"Author Identifier","values":["0000000240846639"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2020-09-15"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Cambridge"]},{"key":"dc:relation.isreferencedby.uri","label":"Dc Relation Isreferencedby URI","values":["https://www.repository.cam.ac.uk/handle/1810/317056"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["oxygen","HIF","metabolism"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/bf262c1d-3776-4add-95b4-b7b3993a80eb/download","https://www.rioxx.net/licenses/all-rights-reserved/"]},{"key":"dc:rights.embargotype","label":"Dc Rights Embargotype","values":["controlled.access"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["10.17863/CAM.64167"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/ae855fef-47a5-4169-9b8d-96699857a5d1/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Oxygen is required for life and is a major determinant of mammalian cell fate. 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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. 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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. 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