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Glutamine, a cellular nutrient, is launching a metabolic signaling pathway that promotes the function of some immune system T cells and suppresses others, researchers at Vanderbilt have discovered.
They show that a drug that inhibits the metabolism of glutamine – currently in clinical trials as an anti-cancer agent – could also be useful in the treatment of inflammatory and autoimmune diseases. The study, published online this week in the journal Cell, also suggests strategies for using the drug to strengthen cancer immunotherapies.
Jeffrey Rathmell, PhD, Professor of Immunobiology Cornelius Vanderbilt, and his colleagues have struggled to understand how a cell integrates its nutrients and metabolism into its function. They had previously demonstrated the importance of glucose in cellular fuel for the activation and function of T cells, responsible for inflammation and the elimination of pathogens.
In the current work, they have turned their attention to another major fuel: glutamine, which has been mainly studied in the context of cancer cell metabolism. Several companies are developing drugs that inhibit the metabolism of glutamine to reduce the growth and proliferation of cancer cells.
Investigators expected that the inhibition of glutamine metabolism – such as blocking glucose metabolism – prevents the activation and function of T lymphocytes. They used a drug that inhibits the first step in the metabolism of glutamine, an enzyme called glutaminase. They also studied mice with a targeted genetic deletion of the glutaminase gene.
The researchers were surprised to find that some T cells – those involved in antiviral and anticancer responses – performed better in the absence of glutaminase activity. Other T cells involved in inflammatory and autoimmune diseases have had worse results.
"We were intrigued by the fact that a metabolic disturbance could have a very different impact on the function of T-cell subsets," said Marc Johnson, a graduate student who led the studies.
The findings are consistent with studies of glutamine metabolism in cancer cells, said Rathmell, also a professor of pathology, microbiology and immunology.
"This compound (which inhibits glutaminase) works in some tumors and does not work in others." What Marc has discovered is that it is the same thing for T cells: some T cells need this way, others do not, "said Rathmell. "If we block the pathway, autoimmune T cells do not perform as well, but anti-cancer T cells do better."
The researchers demonstrated in murine models of allergic asthma, inflammatory bowel disease and chronic graft versus host disease eliminating the activity of glutaminase-protected anti-inflammatory disease. inflammation and disease.
"The glutaminase inhibitor has a remarkable safety profile, and we think it could be reused in a range of inflammatory and autoimmune diseases," said Rathmell.
To examine the impact of glutaminase inhibition on T cells that induce anti-cancer responses, the researchers used the drug in a mouse model of T-cell therapy (chimeric antigen receptor CAR) ). CAR T cells are carcinogenic T cells genetically engineered to recognize specific cancer cells.
In the murine model, the researchers found that treatment with the glutaminase inhibitor improved the function of CAR T cells, but that improved function lost over time. Shorter exposure to the inhibitor improved CAR T cell function, and T cells persisted longer.
"One of the problems of T-cell-based therapy is the survival of modified cells," Johnson said. "We think that a short treatment with a glutaminase inhibitor could improve the persistence of CAR T cells."
The findings have implications for ongoing clinical trials of a glutaminase inhibitor in combination with immunotherapies called checkpoint inhibitors, Rathmell said.
"Our data suggests that the drug combination may work better if you give the glutaminase inhibitor for a short time and then you remove it."
Investigators are testing various dosing regimens in mouse models of cancer.
The researchers also investigated the mechanistic changes resulting from the inhibition of glutaminase and demonstrated that the metabolic pathway of glutamine – generally regarded as energy-generating – is tightly integrated with cellular signaling and at the same time. gene expression.
"By altering this metabolic enzyme, we are affecting a downstream metabolite that directly modifies the accessibility of genes and chromatin as well as the expression of genes," said Rathmell. "As a concept, the idea that metabolic pathways are signaling pathways is relatively new."
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This research was funded by grants from the National Institutes of Health (HL136664, DK105550, CA217987, CA193256, CA001423). Calithera Biosciences has provided a portion of the glutaminase inhibitor for in vitro studies.
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