Santosha Vardhana

Despite the encouraging clinical benefit of treatments that promote immune-mediated control of tumors (immune checkpoint blockade, engineered T-cells), the majority of patients either do not respond or have only transient responses to these treatments, in large part due to persistent T-cell dysfunction. Understanding and targeting T-cell dysfunction in patients with chronic infections and cancer remains an area of substantial clinical need.  We recently discovered that the during the process of repeatedly encountering and attempting to eliminate tumor cells, immune cells develop profound defects in their ability to metabolize available nutrients.  This dysfunctional metabolism directly impairs the ability of immune cells to kill tumor cells (Vardhana et al, Nat Immunol 2020). Our laboratory’s first area of interest is in understanding the specific mechanisms by which T-cell metabolism becomes altered, and how the resultant metabolic alterations activate the global exhaustion program.  We are particularly interested in the following questions: 

1. How do changes in cellular metabolism contribute to the extent to which antigen avidity and dose drive T-cell exhaustion? 
2. What are the epigenetic, post-transcriptional, and post translational mechanisms by which metabolites activate the T-cell exhaustion program?
   
3. How do exhaustion-associated transcription factors, such as TOX, alter intratumoral T-cell metabolism? 

To answer these questions, we have developed novel synthetic platforms that allow us to perform deep metabolic analyses of genetically modified and/or transgenic T-cells. 

Second, members of our laboratory have observed that alterations in the metabolism of immune cells makes them particularly susceptible within the nutrient-poor central regions of tumors, connecting these basic findings to a phenomenon that pathologists have observed for years.  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). A second major area of interest in our lab is therefore to understand the environmental bottlenecks that constrain T-cell function in vivo: 

1. How does nutrient availability in vivo affect intratumoral T-cell metabolism? 
2. How is local nutrient availability affected by tumor stromal composition, tissue residence, and organismal metabolic state? 
3. Can nutrient sensing by T-cells in vivo be inferred by their transcriptional or epigenetic state? 

To answer these questions, we have developed both novel mouse models to track immune responses across distinct cells of origin and tissue residence as well as rapid, high-sensitivity protocols to assess nutrient uptake and utilization from individual cell types within tumors. 

Current Projects: