Nutrient 'tug of war' determines anticancer activity

Scientists at St. Jude Children’s Research Hospital have found that immune and tumour cells compete over glutamine, a major nutrient in their local environment, with significant implications for anticancer activity. If cancer cells monopolise glutamine, they can prevent immune cells from destroying cancer. But if glutamine can be resupplied to the environment, this can be used by the immune cells to initiate cancer-killing activity. The team’s findings were published in the journal Nature.

“It’s a nutrient tug of war between tumour cells and immune cells,” said Dr Hongbo Chi, corresponding author on the study. “If tumour cells use all the available glutamine, then a specialised immune cell type known as the dendritic cell is starved of glutamine, leading to impaired antitumour immune function. But if we can supplement enough glutamine to the tumour microenvironment, that will inhibit tumour growth because dendritic cells will use it and activate the adaptive immune response.”

While much cancer research has focused on T cells because of their direct cancer-killing activity, this study is one of the first to examine how the tumour microenvironment (the area around cancer cells) affects the dendritic cells, which activate the T cells. The researchers found that without glutamine, this activation failed to happen.

“Even though T cells are the cornerstone for anticancer immunity, they cannot do the job by themselves,” Chi explained. “We can think of dendritic cells as the driver and the T cell as the car. If you do not have a driver, the car will not move. Moreover, nutrients like glutamine serve as the licence for the driver.”

Similarly, when the researchers removed the proteins that respond to or take up glutamine in dendritic cells, the immune cells again failed to activate the cancer-killing cells. These proteins, called FLCN and SLC38A2, are important in sensing and acquiring nutrients but have not previously been connected to immune cells’ reactions to tumours. They may thus serve as potent drug targets to improve cancer therapy.

While cancer cells secrete many signals to turn the immune response ‘off’ in the tumour microenvironment, immune checkpoint blockade therapy inhibits these signals. These therapies have been highly effective, but only in a small number of patients. The researchers found that supplying glutamine in combination with checkpoint therapy enhanced anticancer activity in mice.

“We’re extremely excited about these findings,” Chi said. “In addition to enhancing the therapeutic intervention, we have provided a conceptual advance by showing how nutrients mediate cell–cell communication, an understudied concept in the field of immunometabolism.

“This paper provides a proof of concept that nutrients could act synergistically with checkpoint inhibitors for tumour treatment as a new strategy for combination therapy.”

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