Analysis of the effect of the tumour microenvironment on t cell functional phenotype
A successful adaptive immune response requires T cells to be able to adopt a specific metabolic phenotype. However, in
diseases such as cancer or those associated with chronic inflammation, the metabolic microenvironment in which a T cell
functions is likely to subvert this metabolic phenotype, thereby disrupting function.

A better understanding of how the microenvironment can affect T cell function would permit the development of metabolic
'normalising' treatments that could restore function and permit disease resolution.

However, there is currently a disconnect within the field of immunometabolism that requires high resolution, direct analyses
of T cell metabolism in order to solve. We therefore propose an approach that uses stable isotope-enriched metabolites that
are associated with immunosuppressive cancer microenvironments (e.g. 13C3-lactate) to trace their use in different T cell
populations (isolated from healthy peripheral blood), and thereby identify the precise pathway by which they are metabolised
and how this alters cytotoxic function and proliferative capacity. By inhibiting the metabolic pathway implicated either
pharmacologically, or using physiologically relevant stimuli (e.g. hypoxia), we will unequivocally link use of specific
immunomodulatory metabolites, such as lactate, succinate and citrate, with T cell function.