Inhibition of Glutamine Metabolism Improving the Efficacy of CAR-T Cell Immunotherapy
Jeffrey Rathmell, Ph.D., professor of immuno-biology at Vanderbilt university in the United States, and his colleagues have previously shown that cellular fuel glucose plays an important role in the activation and function of t-cells that promote inflammation and eliminate pathogens.
In a new study, Rathmell's team turned their attention to another major fuel: glutamine. They demonstrated that glutamine activates a metabolic signaling pathway that promotes the functioning of some T cells and inhibits the functioning of others. Relevant research results were published online in the journal Cell on November 1, 2018, with the title "Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism".
These researchers originally expected to inhibit glutamine metabolism as blocking glucose metabolism and prevent T cell activation and function. They used a drug to inhibit glutaminase, an enzyme involved in the first step of glutamine metabolism. They also studied mice whose glutaminase coding genes had been targeted for deletion.They were surprised to find that in these mice, certain t-cells - those that mediate antiviral and anticancer responses - performed better in the absence of glutaminase activity.
Rathmell said the findings are consistent with previous studies of glutamine metabolism in cancer cells.
The researchers also investigated changes in the mechanism caused by glutamine enzyme inhibition and confirmed that the glutamine metabolic pathway, which is generally thought to produce only energy, is closely associated with cellular signal transduction and gene expression.
“By altering this metabolic enzyme, we influence a downstream metabolite that directly changes chromatin/gene accessibility and gene expression. As a concept, the idea that metabolic pathways are signaling pathways is relatively new”, Rathmell said.
In a new study, Rathmell's team turned their attention to another major fuel: glutamine. They demonstrated that glutamine activates a metabolic signaling pathway that promotes the functioning of some T cells and inhibits the functioning of others. Relevant research results were published online in the journal Cell on November 1, 2018, with the title "Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism".
These researchers originally expected to inhibit glutamine metabolism as blocking glucose metabolism and prevent T cell activation and function. They used a drug to inhibit glutaminase, an enzyme involved in the first step of glutamine metabolism. They also studied mice whose glutaminase coding genes had been targeted for deletion.They were surprised to find that in these mice, certain t-cells - those that mediate antiviral and anticancer responses - performed better in the absence of glutaminase activity.
Rathmell said the findings are consistent with previous studies of glutamine metabolism in cancer cells.
The researchers also investigated changes in the mechanism caused by glutamine enzyme inhibition and confirmed that the glutamine metabolic pathway, which is generally thought to produce only energy, is closely associated with cellular signal transduction and gene expression.
“By altering this metabolic enzyme, we influence a downstream metabolite that directly changes chromatin/gene accessibility and gene expression. As a concept, the idea that metabolic pathways are signaling pathways is relatively new”, Rathmell said.
