Researchers at the UNC Lineberger Comprehensive Cancer Center have identified an enzyme that saps the energy of T cells once they have infiltrated a solid tumor and prevents them from effectively combatting cancer. The team found that the metabolic enzyme, called Acetyl-CoA Carboxylase (ACC) is turned “on” in the tumor environment which causes T cells to store lipids rather than burning them for energy.
“Our discovery fills a long-standing gap in knowledge regarding why T cells in solid tumors don’t appropriately generate energy,” said Jessica Thaxton, PhD, associate professor of cell biology and physiology and co-leader of the Cancer Cell Biology Program at Lineberger. “We inhibited the expression of ACC in mouse cancer models, and we observed that T cells were able to persist much better in solid tumors.”
This finding, published in the journal Cell Metabolism, could be used to create multiple types of new T-cell therapies for combatting a range of cancers and potentially encompassing both immune checkpoint drugs and chimeric antigen receptor (CAR) T-cell therapies.
The latest research from Thaxton’s lab sought to discover why T cells within a solid tumor are not about to create their cellular energy, called adenosine triphosphate (ATP).
In early research the lab studied a T cell that had optimal antitumor activity. That research, published in Cancer Immunology Research, looked to identify enzymes that were associated with optimal antitumor metabolism in T cells. In this research it was revealed that ACC expression may limit the ability of T cells to make ATP. ACC is an important molecule involved in multiple metabolic pathways and blocks cells from breaking down fats and using it as fuel for energy in mitochondria.
“Acetyl-CoA carboxylase can drive the balance between storing lipids versus breaking down those lipids and feeding them into the citric acid cycle for energy,” explained Thaxton. “If ACC is flipped ‘on’, cells generally store lipid. If ACC is ‘off’, cells tend to use the lipid in their mitochondria to make ATP.”
Using confocal imaging, the investigators observed lipid stores in T cells that were isolated from multiple types of cancer. Combined with other experiments this confirmed the hypothesis that T cells were storing lipids rather than breaking them down for energy.
Using CRISPR/Cas9, the team then sought to see what would happen if they “deleted” ACC. They found a rapid reduction in the level of lipid storage in T cells and were also able to visualize the fat relocating to the mitochondria to be used to generate energy.
According to Thaxton, the research suggests that T cells may need to find a balance of lipids to persist within the tumor environment—some with a certain amount of lipid focused on attacking cancer cells and low levels of fats maintained in stores.
The findings have significant implications for refining cancer immunotherapy, as Thaxton’s lab is now researching ways it might be able to flip the ACC metabolic switch directly in the tumors themselves which could render the need to remove, then reinfuse engineered T cells back into a patient to fight their cancer. First steps in this discovery process is to determine how manipulating ACC could affect other immune cell populations in the body.
