Friday, May 9, 2025
5/9/2025
Glycolysis and Glutaminase in CD8 T cell differentiation and anti-tumor immunity - Summary Immunotherapy has transformed cancer treatment and improved clinical outcomes, but it does not cure most patients. Treatments such as anti-PD1 monoclonal antibodies and chimeric antigen receptor (CAR) T cells function by boosting the activity of cancer-specific interferon gamma-producing Th1 CD4 T cells and cytotoxic CD8 T cells (CTL). Increased effector function, however, must be balanced with the ability of anti- cancer T cells to persist long-term. A key goal of immunotherapy is to enhance effector function while maintaining T cell longevity and memory. It is now clear from work in the Rathmell lab that effector T cells utilize high rates of glycolysis while memory cells utilize mitochondrial pathways. Here I propose to test cell metabolism as a means to enhance both effector and memory T cell populations in immunotherapy. T cells radically alter their metabolism upon activation and increase glycolysis and glutamine oxidation (glutaminolysis) to support differentiation, effector function, and eventual generation of long-term memory that depend on mitochondria. Modulation of T cell glutamine metabolism may augment the efficacy of immunotherapy by enhancing both T cell effector function or memory capacity. The Rathmell Lab has shown that the metabolic program aerobic glycolysis is essential for effector T cell (Teff) function in inflammation and in tumors. Glutaminolysis complements glycolysis to fuel T cells by converting glutamine to the tricarboxylic acid cycle intermediate alpha-ketoglutarate (aKG). Using a conditional knockout of the glutaminolysis enzyme Glutaminase (GLS), which converts glutamine to glutamate, and an inhibitor of GLS that is currently in clinical trials as an anti-cancer agent, we have found that inhibition of GLS leads to a compensatory increase in glycolysis that enhances Th1 and CTL Teff function and differentiation. In addition to increasing effector function, however, I found that GLS inhibition also increases expression of inhibitory receptors, and chronic GLS deficiency ultimately suppresses T cells. In contrast, transient GLS inhibition enhanced Teff function while also priming mitochondrial metabolism for a memory-like differentiation, and led to improved T cell persistence in vivo. In this proposal, I will test the hypothesis that transient GLS inhibition can augment Teff function and maintain T cell survival and memory to boost anti-cancer immunotherapy efficacy, whereas chronic GLS inhibition will drive compensatory glycolysis, terminal Teff differentiation, and exhaustion. I will: (1) Test how transient versus chronic GLS inhibition affects CTL fate by determining differences in memory T cell formation, assessing the contribution of compensatory glycolysis to Teff phenotypes, and establishing the mitochondrial consequences of GLS inhibition; and (2) Test the effect of GLS inhibition on the immunotherapy efficacy of CD19-targeted CAR T cells and anti-PD1 treatment. These studies will demonstrate a new approach to improve anti-cancer immunotherapy and highlight a strategy of using GLS inhibition to modulate T cell metabolism and differentiation.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).