T cell metabolism and immunotherapy

Research lines

The Foskolou lab is establishing a research line on T cell metabolism and cancer immunotherapy. The lab aims to improve CAR (chimeric antigen receptor) T cell therapy against solid tumours by better understanding the environment CAR-T cells face both in tumours and in lymphoid organs. Our 2 main research lines are:

1) Understanding how T cells respond to low oxygenation (hypoxia)

Oxygen regulates cell metabolism, function, differentiation, and survival of immune cells. Circulating T cells encounter a wide range of oxygen levels during circulation, since most lymphoid tissues are naturally hypoxic (bone marrow 6% O2, spleens 2.9% O2, thymus 0-2% O2). T cells also face oxygen limitation in solid tumours and inflammatory tissues. Hypoxia affects T cell metabolism, function, and differentiation but the effect of hypoxia on T cell responses is rarely investigated. The Foskolou group aims to determine how low oxygenation can be used to achieve beneficial T cell responses, and to find the mechanisms underlying how severe and continuous hypoxia becomes detrimental. We have recently shown that hypoxia and hypoxia-induced metabolites can alter the T cell differentiation status and enhance anti-tumour activity in CAR-T cell therapies. Uncovering the mechanisms by which hypoxia has both beneficial and detrimental effects can help to design better CAR-T cells with higher persistence and to understand how these CAR-T cells can better handle the tumour microenvironment.

2) Finding new CAR-T cell production methods to increase therapy outcome

We recently showed that CAR-T cells that are maintained in a less differentiated phenotype (i.e., multipotent or central memory T cells) during manufacturing display better expansion, anti-tumour activity and persistence. To create multipotent and central memory CAR-T cells we either genetically modify the CAR-T cells using CRISPR/Cas 9 gene editing or we treat the CAR-T cells with specific inhibitors and metabolites. The targets we currently investigate are epigenetic (TET2, KDMs) and epitranscriptomic modifiers (METTL3, FTO, ALKBH5). Optimising the CAR-T cell culturing and manufacturing conditions has strong potential to advance CAR-T cell immunotherapy.