Dr. Jeffrey Rathmell, professor of immunobiology at Vanderbilt University in the United States, and his colleagues have previously demonstrated that cell fuel glucose plays an important role in promoting inflammation and clearing the activation and function of pathogenic T cells.
In a new study, Rathmell's team turned their attention to another major fuel: glutamine. They confirmed that glutamine triggers a metabolic signaling pathway that promotes the functioning of some T cells and inhibits the functioning of other T cells.
These researchers had hoped that inhibiting glutamine metabolism would block the activation and function of T cells just like blocking glucose metabolism. They used a drug to inhibit glutaminase, the first step in glutamine metabolism. They also studied mice whose glutaminase-coding genes were targeted for elimination. They were surprised to find that some T cells in these mice, those that mediate antiviral and anticancer responses, performed better in the absence of glutaminase activity. Other T cells involved in inflammatory and autoimmune diseases performed poorly.
These researchers demonstrated that glutaminase clearance can prevent inflammation and disease in mice with allergic asthma, inflammatory bowel disease and chronic graft-versus-host disease. This glutaminase inhibitor has significant safety and is expected to change its use to potentially treat a range of inflammatory and autoimmune diseases.
To investigate the effects of glutaminase inhibition on T cells mediating anticancer responses, these researchers used glutaminase inhibitors in mice models receiving CAR (chimeric antigen receptor) T cells (CAR-T cells) immunotherapy. CAR-T cells are T cells that specifically recognize cancer cells after genetic modification and have cancer killing capacity. In this mouse model, they found that treatment with this glutaminase inhibitor enhanced the function of CAR-T cells, but this enhanced function was lost after a period of time. Shorter exposure to this glutaminase inhibitor can improve the function of CAR-T cells, and CAR-T cells can last longer.
Rathmell said these findings have a significant impact on current clinical trials of glutaminase inhibitors in combination with immunotherapeutic drugs known as immunocheckpoint inhibitors.
The researchers also explored changes in the mechanism caused by glutaminase inhibition and confirmed that the pathway of glutamine metabolism, which is usually thought to produce only energy, is closely linked to cell signaling and gene expression.
By altering this metabolic enzyme, we affect a downstream metabolite that directly alters chromatin/gene accessibility and gene expression. As a concept, the idea that metabolic pathways are signaling pathways is relatively new.
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