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The role of hypoxia in T cell function and immunotherapy 10.17863/CAM.90501 Pacheco de Jesus da Cunha, Pedro Miguel Johnson, Randall S Branco, Cristina Velica, Pedro 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. University of Cambridge 2022-07-31 Thesis Doctoral Doctor of Philosophy (PhD) eng Portuguese Foundation for Science and Technology scholarship SFRH/BD/115612/2016 https://www.repository.cam.ac.uk/handle/1810/343090 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/70b465c0-c494-435c-86b8-79339d5e88e5/download f96342a6e266d677feb86e9ebe6d8bf0 https://www.rioxx.net/licenses/all-rights-reserved/ CAR-T cell therapy CD8+ T cells Glutarate Hypoxia Immunology Immunometabolism Immunotherapy Nitric oxide