The role of hypoxia in T cell function and immunotherapy
type: CreativeWork
description: 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 CD…
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 CD…
author: Pacheco de Jesus da Cunha, Pedro Miguel
language: eng
keywords: CAR-T cell therapy, CD8+ T cells, Glutarate, Hypoxia, Immunology, Immunometabolism, Immunotherapy, Nitric oxide
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2022-07-31
date modified: 2026-07-22T22:24:03Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.90501