Molecular Regulation Of Immune Metabolism
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:
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.
Environmental Control Of Immune Function
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:
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.
Metabolic Drivers Of Immune Heterogeneity
In the past five years, single-cell genomics has revealed tremendous heterogeneity within tumor-infiltrating immune cells and particularly within tumor-resident T-cells. Whether this functional heterogeneity is accompanied by metabolic heterogeneity is unknown. We aim to combine single cell genomics with synthetic biology to identify metabolic hallmarks of discrete immune cell populations within tumors:
1. Can we define discrete transcriptional and epigenetic programs of conventional and exhausted T-cells during select nutrient limitations?
2. Do tumor-infiltrating T-cells within different tumors and/or different tissues selectively express these metabolic gene expression and/or chromatin signatures?
3. Can we combine this information with targeted CRISPR screens to map the altered differentiation of T-cells within distinct tumor types and identify tumor specific targets to enhance immunotherapy?
We are actively combining our novel synthetic platforms with single cell genomic approaches to both identify and target metabolic liabilities of specific immune cell subsets across different tissues and malignancies.
Immune Dysregulation in Hematologic Malignancies
Malignant transformation of hematopoietic cell subtypes significantly alters the non-transformed immune cell population, with profound implications for host immunity to both pathogens and hemapoietic cancers. Specific interests of the laboratory include:
1. How does B-cell depletion affect T-cell responses to both viral infections and cancers?
2. How can we enhance immune-mediated therapies in patients with hematopoietic malignancies?
Our laboratory-based investigations in these areas leverage knowledge from the mechanistic research we pursue using model systems and apply those principles to primary patient samples.