{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/343090"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/343090","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"The role of hypoxia in T cell function and immunotherapy","abstract":"Oxygen deprivation (hypoxia) is an important immunosuppressive mechanism in cancer. The lack of proper blood supply and a high local metabolic demand depletes immune cells of key metabolites including oxygen. Tumour hypoxia is particularly hostile to antitumour cytotoxic CD8+ T cell function by repressing clonal expansion and by eliciting immune checkpoint mechanisms. However, T cells cultured ex vivo at low levels of oxygen outperform ambient oxygen-cultured counterparts in terms of antitumour cytotoxic function following adoptive cell transfer to a tumour-bearing host. This indicates that hypoxia can play a physiological role in regulating and, depending on the context, boosting T cell function. This dissertation is divided into 3 chapters, each dedicated to describing different physiological roles of hypoxia in CD8+ T cells. Chapter 1 addresses the role of oxygen sensing by the HIF pathway in fueling the hypoxia-driven increase in CD8+ T cell function in adoptive cell transfer settings. Increased HIF signalling achieved through genetic or pharmacological manipulation of the HIF pathway shaped T cell function and differentiation in a similar manner to exposure to low oxygen tensions. Exacerbated HIF signalling was immunosuppressive whereas a controlled or temporary increase in HIF activity was immunomodulatory and improved the cytotoxic function of CAR-T cells. A single day of hypoxia-conditioning during T cell activation followed by 6 days of expansion in ambient oxygen, was sufficient to modulate metabolism, differentiation and to improve in vivo antitumour cytotoxicity of CAR-T cells, thus showing the power of oxygen tensions in shaping T cell function. Chapter 2 focuses on the metabolic adaptation to low oxygen in CD8+ T cells, and characterises the immunomodulatory role of glutarate, a newly discovered hypoxia-induced metabolite. Glutarate was found to inhibit α-ketoglutarate dependent reactions and to modulate T cell differentiation and improve antitumour CD8+T cell function. Administration of esterified glutarate in tumour-bearing animals significantly improved infiltration of CD8+ T cells in tumours and extended animal survival, thus revealing the potential of glutarate to be used as a metabolic target. Chapter 3 describes the role of nitric oxide, another hypoxia-induced metabolite, in T cell function. Nitric oxide was found to be endogenously produced by T cells and to mediate their tissue infiltration and antitumour function. Overall, the data presented here show how oxygen tensions can profoundly shape T cell function through modulation of T cell differentiation and metabolism and informs about new strategies of T cell modulation that can improve immunotherapy.","abstract_html":"Oxygen deprivation (hypoxia) is an important immunosuppressive mechanism in cancer. The lack of proper blood supply and a high local metabolic demand depletes immune cells of key metabolites including oxygen. Tumour hypoxia is particularly hostile to antitumour cytotoxic CD8+ T cell function by repressing clonal expansion and by eliciting immune checkpoint mechanisms. However, T cells cultured ex vivo at low levels of oxygen outperform ambient oxygen-cultured counterparts in terms of antitumour cytotoxic function following adoptive cell transfer to a tumour-bearing host. This indicates that hypoxia can play a physiological role in regulating and, depending on the context, boosting T cell function. This dissertation is divided into 3 chapters, each dedicated to describing different physiological roles of hypoxia in CD8+ T cells. Chapter 1 addresses the role of oxygen sensing by the HIF pathway in fueling the hypoxia-driven increase in CD8+ T cell function in adoptive cell transfer settings. Increased HIF signalling achieved through genetic or pharmacological manipulation of the HIF pathway shaped T cell function and differentiation in a similar manner to exposure to low oxygen tensions. Exacerbated HIF signalling was immunosuppressive whereas a controlled or temporary increase in HIF activity was immunomodulatory and improved the cytotoxic function of CAR-T cells. A single day of hypoxia-conditioning during T cell activation followed by 6 days of expansion in ambient oxygen, was sufficient to modulate metabolism, differentiation and to improve in vivo antitumour cytotoxicity of CAR-T cells, thus showing the power of oxygen tensions in shaping T cell function. Chapter 2 focuses on the metabolic adaptation to low oxygen in CD8+ T cells, and characterises the immunomodulatory role of glutarate, a newly discovered hypoxia-induced metabolite. Glutarate was found to inhibit α-ketoglutarate dependent reactions and to modulate T cell differentiation and improve antitumour CD8+T cell function. Administration of esterified glutarate in tumour-bearing animals significantly improved infiltration of CD8+ T cells in tumours and extended animal survival, thus revealing the potential of glutarate to be used as a metabolic target. Chapter 3 describes the role of nitric oxide, another hypoxia-induced metabolite, in T cell function. Nitric oxide was found to be endogenously produced by T cells and to mediate their tissue infiltration and antitumour function. Overall, the data presented here show how oxygen tensions can profoundly shape T cell function through modulation of T cell differentiation and metabolism and informs about new strategies of T cell modulation that can improve immunotherapy.","abstract_has_math":false,"creators":["Pacheco de Jesus da Cunha, Pedro Miguel"],"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 S","Branco, Cristina","Velica, Pedro"],"committee_chairs":[],"committee_members":[],"year":2022,"date_issued":"2022-07-31","date_published":"2022-07-31","updated_at":"2026-07-22T22:24:03Z","subjects":["CAR-T cell therapy","CD8+ T cells","Glutarate","Hypoxia","Immunology","Immunometabolism","Immunotherapy","Nitric oxide"],"languages":["eng"],"rights":[],"rights_urls":["https://www.rioxx.net/licenses/all-rights-reserved/"],"identifier_entries":[]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.90501","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Johnson, Randall S","Branco, Cristina","Velica, Pedro"]},{"key":"dc:contributor.sponsor","label":"Sponsor","values":["Portuguese Foundation for Science and Technology scholarship SFRH/BD/115612/2016"]},{"key":"dc:creator","label":"Author","values":["Pacheco de Jesus da Cunha, Pedro Miguel"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2022-07-31"]},{"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/1810/343090"]},{"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":["CAR-T cell therapy","CD8+ T cells","Glutarate","Hypoxia","Immunology","Immunometabolism","Immunotherapy","Nitric oxide"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["https://www.rioxx.net/licenses/all-rights-reserved/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["10.17863/CAM.90501"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/70b465c0-c494-435c-86b8-79339d5e88e5/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Oxygen deprivation (hypoxia) is an important immunosuppressive mechanism in cancer. 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Increased HIF signalling achieved through genetic or pharmacological manipulation of the HIF pathway shaped T cell function and differentiation in a similar manner to exposure to low oxygen tensions. Exacerbated HIF signalling was immunosuppressive whereas a controlled or temporary increase in HIF activity was immunomodulatory and improved the cytotoxic function of CAR-T cells. A single day of hypoxia-conditioning during T cell activation followed by 6 days of expansion in ambient oxygen, was sufficient to modulate metabolism, differentiation and to improve in vivo antitumour cytotoxicity of CAR-T cells, thus showing the power of oxygen tensions in shaping T cell function. Chapter 2 focuses on the metabolic adaptation to low oxygen in CD8+ T cells, and characterises the immunomodulatory role of glutarate, a newly discovered hypoxia-induced metabolite. Glutarate was found to inhibit α-ketoglutarate dependent reactions and to modulate T cell differentiation and improve antitumour CD8+T cell function. Administration of esterified glutarate in tumour-bearing animals significantly improved infiltration of CD8+ T cells in tumours and extended animal survival, thus revealing the potential of glutarate to be used as a metabolic target. Chapter 3 describes the role of nitric oxide, another hypoxia-induced metabolite, in T cell function. Nitric oxide was found to be endogenously produced by T cells and to mediate their tissue infiltration and antitumour function. 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Increased HIF signalling achieved through genetic or pharmacological manipulation of the HIF pathway shaped T cell function and differentiation in a similar manner to exposure to low oxygen tensions. Exacerbated HIF signalling was immunosuppressive whereas a controlled or temporary increase in HIF activity was immunomodulatory and improved the cytotoxic function of CAR-T cells. A single day of hypoxia-conditioning during T cell activation followed by 6 days of expansion in ambient oxygen, was sufficient to modulate metabolism, differentiation and to improve in vivo antitumour cytotoxicity of CAR-T cells, thus showing the power of oxygen tensions in shaping T cell function. Chapter 2 focuses on the metabolic adaptation to low oxygen in CD8+ T cells, and characterises the immunomodulatory role of glutarate, a newly discovered hypoxia-induced metabolite. Glutarate was found to inhibit α-ketoglutarate dependent reactions and to modulate T cell differentiation and improve antitumour CD8+T cell function. Administration of esterified glutarate in tumour-bearing animals significantly improved infiltration of CD8+ T cells in tumours and extended animal survival, thus revealing the potential of glutarate to be used as a metabolic target. Chapter 3 describes the role of nitric oxide, another hypoxia-induced metabolite, in T cell function. Nitric oxide was found to be endogenously produced by T cells and to mediate their tissue infiltration and antitumour function. 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