A new study in mice by scientists at St. Jude Children’s Research Hospital reveals that immune and tumor cells compete over glutamine. The researchers also identified a molecular pathway that could serve as a potential drug target to achieve the same effect.
The findings are published in Nature in an article titled, “SLC38A2 and glutamine signaling in cDC1s dictate anti-tumor immunity.”
“Cancer cells evade T cell-mediated killing through tumor–immune interactions whose mechanisms are not well understood,” the scientists wrote. “Dendritic cells (DCs), especially type-1 conventional DCs (cDC1s), mediate T cell priming and therapeutic efficacy against tumors. DC functions are orchestrated by pattern recognition receptors, although other signals involved remain incompletely defined. Nutrients are emerging mediators of adaptive immunity, but whether nutrients affect DC function or communication between innate and adaptive immune cells is largely unresolved. Here we establish glutamine as an intercellular metabolic checkpoint that dictates tumor–cDC1 crosstalk and licenses cDC1 function in activating cytotoxic T cells.”
“It’s a nutrient tug-of-war between tumor cells and immune cells,” said corresponding author Hongbo Chi, PhD, St. Jude department of immunology. “If tumor cells use all the available glutamine, then a specialized immune cell type known as the dendritic cell is starved of glutamine, leading to impaired anti-tumor immune function. But if we can supplement enough glutamine to the tumor microenvironment, that will inhibit tumor growth because dendritic cells will use it and activate the adaptive immune response.”
The scientists demonstrated that resupplying glutamine in the tumor microenvironment reduced tumor growth because dendritic cells were then better able to activate anticancer T cells. The St. Jude team is the first to identify a nutrient as a major signal between cancer cells and dendritic cells in this local environment.
“We are very excited to establish the link between glutamine, therapeutic effect, and dendritic cells,” said first author Chuansheng Guo, PhD, St. Jude department of immunology. “It’s critical for the efficacy of immune checkpoint blockade and adoptive cell transfer therapy.”
The scientists also discovered 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.”