Enzyme Identified That Saps T Cells’ Ability to Attack Solid Tumors

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.

https://www.insideprecisionmedicine...-saps-t-cells-ability-to-attack-solid-tumors/

 

Highlights

• The tumor microenvironment induces lipid droplet (LD) accumulation in dysfunctional CD8+ TILs
• Acetyl-CoA carboxylase (ACC) directs LD accumulation in CD8+ T cells
• Inhibition of ACC in CD8+ T cells facilitates fatty acid oxidation
• Restraining ACC promotes CD8+ TIL persistence and tumor control
  

Study