T cells, in particular CD8+ T cells, play a critical role in maintaining immune homeostasis and in eliminating cancerous cells. In recent years it has emerged that cellular metabolism is a central regulator of T cell fate and function. T cell metabolic profiles rapidly fluctuate following T cell activation and can be highly influenced by microenvironmental factors, such as oxygen. This work explores the intertwining role of metabolism and oxygen in CD8+ T cell differentiation and anti-tumour immunity, with a particular emphasis on designing novel cancer immunotherapies.

This thesis comprises four results chapters, the first three of which are centred around the metabolite glutarate, an oxygen sensitive metabolite with no known immunological function prior to this work. Chapter III identifies glutarate as an endogenous regulator of T cell function, demonstrating its capacity to enhance CD8+ T cell cytotoxicity and reduce tumour growth. Chapter IV identifies glutarate as a competitive inhibitor of alpha-ketoglutarate dependent dioxygenases (αKGDDs) and explores the effect of glutarate on hypoxia-inducible factor prolyl-hydroxylases (PHDs) and on DNA and histone methylation. Chapter V focuses on the role of glutarate in cellular metabolism and reveals that glutarate controls the activity of the pyruvate dehydrogenase complex (PDHc) via the post-translational modification glutarylation. The final results chapter, Chapter VI, focuses on the role of molecular oxygen as a regulator of T cell activation and metabolic reprogramming. This chapter further explores manipulation of oxygen sensing pathways for therapeutic gain in the context of cancer.

The data presented here describe glutarate as an important metabolite with significant T cell modulatory capacity whilst also highlighting the important role of molecular oxygen in T cell activation and differentiation. Furthermore, this work highlights the important interplay between metabolism and oxygenation in T cells and illustrates that harnessing these pathways can improve anti-tumour immunity, with potential clinical importance.