We have identified altered cellular metabolism as a fundamental driver of T-cell exhaustion (Vardhana et al, Nat Immunol 2020). We now aim to understand the specific mechanisms by which T-cell metabolism becomes altered, and how the resultant metabolic alterations activate the global exhaustion program.

We and others have found that local nutrient availability can significantly alter cellular function and identity by effecting changes in the concentrations of intracellular metabolites (Vardhana et al, Nat Metabolism 2019).  We aim to understand how this modifies T-cell function in vivo.

In the past five years, single-cell genomics has revealed tremendous heterogeneity within tumor-infiltrating immune cells and particularly within tumor-resident T-cells.