The effect of hypoxia on the tumour microenvironment

Abstract

An area of interest in cancer therapeutics is identifying the mechanisms of tumour-mediated immune suppression and the role of oxygen to both tumour cells and CD8⁺ cytotoxic T-lymphocytes (CTLs). In hypoxic conditions, hypoxia-inducible factor 1 (HIF-1) is stabilised and transcriptionally activates hypoxia response elements. The cytolytic activity and metabolic profiles of CTLs in hypoxic conditions within a tumour microenvironment (TME) remains uncertain and better understanding is increasingly important in the study of cancer therapy. To investigate the effects of hypoxia on the cytotoxicity of CTLs, we determined the rate of tumour cell killing by CTLs upon HIF-1 stabilisation by cobalt (II) chloride (CoCl₂) treatment or exposure to a hypoxic environment. Acute and 24-hour pre-incubation treatments of CoCl₂ and hypoxia did not influence the rate of tumour cell killing. Upon inhibition of glycolysis using 2-deoxy-D-glucose (2-DG), CoCl₂ pre-incubation also did not affect CTL cytotoxicity. Metabolic stress assays on CTLs given CoCl2 pre-treatment resulted in reduced mitochondrial oxidative phosphorylation (OXPHOS), whereas the hypoxia pre-treatment suppressed overall cellular metabolism. Thus, hypoxia exposure reduced CTL metabolism without permanently diminishing its cytolytic ability.

Date of Award	22 Mar 2022
Original language	English
Awarding Institution	University of Bristol
Supervisor	Christoph Wuelfing (Supervisor) & David J Morgan (Supervisor)