Scientists aim to understand why T cells do not conserve energy in tumors

T cells are often called “killers” or “killers” because they can orchestrate and carry out missions to hunt down bacteria, viruses and cancer cells throughout the body. As powerful as they are, recent research has shown that once T cells infiltrate the environment of a solid tumor, they lose the energy needed to fight cancer.

A research team led by Jessica Thaxton, PhD, MsCR, associate professor of cell biology and physiology and co-head of the Cancer Cell Biology Program at the UNC Lineberger Comprehensive Cancer Center, aimed to understand why T cells fail to conserve energy in tumors. Using their expertise in immunity and tumor metabolism, the Thaxton Lab, led by Katie Hurst, MPH, and 4^u student Ellie Hunt, discovered that a metabolic enzyme called acetyl-CoA carboxylase (ACC) causes T cells to store fat instead of burning fat for energy.

Our discovery fills a long-standing gap in knowledge about why T cells in solid tumors do not properly generate energy. We inhibited ACC expression in mouse cancer models and observed that the T cells were able to persist much better in solid tumors.”

Jessica Thaxton, PhD, MsCR, associate professor of cell biology and physiology and co-head of the Cancer Cell Biology Program at UNC Lineberger Comprehensive Cancer Center

The new findings and immunotherapeutic strategies, published in Cellular Metabolismcould be used to make multiple types of T-cell therapies more effective for patients, potentially 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 unable to generate their cellular energy, called adenosine triphosphate, or ATP, when inside a solid tumor.

In 2019, Thaxton’s lab studied a T cell with optimal anti-tumor function. In a publication at Cancer Immunology Research, Hurst and Thaxton used a proteomics screen to identify enzymes associated with optimal antitumor metabolism of these T cells. Through this examination, the two discovered that ACC expression can limit the ability of T cells to produce 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 storing lipids versus breaking down those lipids and feeding them into the citric acid cycle for energy,” Thaxton said. “If ACC is activated, cells generally store lipids. If ACC is ‘off’, cells tend to use the lipid in their mitochondria to make ATP.”

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

Thaxton’s team then used CRISPR Cas9-mediated gene deletion to see what would happen if they “deleted” ACC from the picture. There was a rapid decrease in the amount of lipid storage in the T cells, and the team was able to visualize the fat being relocated to the mitochondria to be used for energy production.

Thaxton now hypothesizes that T cells may need a “delicate balance” of lipids to persist in solid tumors with a certain amount of lipid dedicated to killing cancer cells and low levels of lipids maintained in stores.

The latest findings could prove useful in enhancing chimeric antigen receptor (CAR) T-cell therapies. This cutting-edge technology removes T cells from cancer patients, modifies them in the lab to hunt cancer cells, and then re-injects the cells to fight the patient’s cancer. Preliminary data from Thaxton’s lab show that even engineered T cells contain excess lipid stores.

The lab is beginning to examine patient samples to understand how researchers can potentially flip the ACC metabolic switch directly in patient tumors, negating the need to remove and re-inject cells back into the body. But researchers must first determine how this might affect other populations of immune cells in the body, such as macrophages.