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Health News Here’s Why Killer T Cells in Solid Tumors Lose Power, According to Research

As powerful as T cells can be, current research shows that once they enter the solid tumor environment, they lose the energy they need to fight malignancy.

A research team led by Jessica Thaxton, PhD, MSCR, associate professor of cell biology and physiology and co-leader of the Cancer Cell Biology Program at the UNC Lineberger Comprehensive Cancer Center, aimed to understand why T cells do not maintain strength in tumors. Using their expertise in tumor immunity and metabolism, the Thaxton lab, led by Katie Hurst, MPH, and 4th-year graduate student Eli Hunt, discovered that a metabolic enzyme called Acetyl-CoA Carboxylase (ACC) prevents T cells from storing fat. Burn fat for energy.

“Our discovery fills a long-standing gap in knowledge about why T cells in solid tumors do not generate energy appropriately,” Thaxton said. “We inhibited the expression of ACC in mouse cancer models, and we observed that T cells were able to migrate better to solid tumors.”

New discoveries and immunotherapeutic strategies published in Cell Metabolism could be used to make multiple types of T-cell therapies more effective for patients, possibly including both checkpoint and chimeric antigen receptor (CAR) T-cell therapies.

In the field of cancer immunotherapy, it has long been known that T cells are not able to produce their cellular energy, called adenosine triphosphate or ATP, when they are inside a solid tumor.

In 2019, Thaxton’s lab studied a T cell with optimal antitumor function. In a publication in Cancer Immunology Research, Hurst and Thaxton used a proteomics screen to identify enzymes associated with optimal antitumor metabolism of these T cells. Through this screen, the two discovered that ACC expression can limit the ability of T cells to generate ATP in tumors. ACC, a key molecule involved in many metabolic pathways, prevents cells from breaking down fat and using it as fuel for energy in the mitochondria.

“Acetyl-CoA carboxylase can drive the balance between preserving lipids versus breaking down those lipids and feeding them into the citric acid cycle for energy,” Thaxton says. “If ACC is turned ‘on’, cells normally store lipids. If ACC is ‘off’, cells use lipids in their mitochondria to make ATP.”

Using Hunt’s expertise in confocal imaging, the research team was able to observe lipid stores in T cells isolated from multiple types of cancer. The observation, as well as other experiments, confirmed the team’s hypothesis that the T cells were storing lipids rather than breaking them down.

Thaxton’s team then used the CRISPR Cas9-mediated gene deletion method to see what would happen if they “removed” ACC from the picture. The amount of lipid storage in the T cells rapidly decreased, and the team was able to visualize the transfer of fat to the mitochondria to be used to generate energy.

Thaxton now hypothesizes that T cells may need a “fine balance” of lipids to survive in solid tumors and have a certain amount of lipids dedicated to killing cancer cells and less fat in stores.
The latest findings may be useful in improving chimeric antigen receptor (CAR) T-cell therapy. This cutting-edge technology takes T cells from cancer patients, modifies them in the lab to seek out tumor cells, and then reinjects the cells to fight the patient’s cancer. Preliminary data from Thaxton’s lab demonstrate that even produced T cells have excess lipid stores.

The lab has begun looking at patient samples to understand how researchers can flip the ACC metabolic switch directly in a patient’s tumor, negating the need to take the cells back and reintroduce them into the body. But researchers first need to determine how it might affect other immune cell populations in the body, such as macrophages.

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