T cells are commonly called “killers” or “killers” because they can plan and execute missions to hunt down bacteria, viruses, and cancer cells throughout the body. No matter how powerful T cells are, current research has shown that once they enter the environment of a solid tumor, they lose the energy needed to fight the 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 Linebarger Comprehensive Cancer Center, aimed to understand why T cells do not maintain energy in tumors. Are. Using their expertise in tumor immunity and metabolism, the Thaxton lab, led by Katie Hurst, MPH, and fourth-year graduate student Ellie Hunt, discovered that a metabolic enzyme called acetyl-CoA carboxylase (ACC) causes T cells to store fat. Causes fat to be stored instead. Burning fat for energy.
“Our discovery fills a long-standing gap in the knowledge about why T cells in solid tumors do not appropriately generate energy,” Thaxton said. “We blocked the expression of ACC in a mouse cancer model, and we saw that the T cells were able to survive much better in solid tumors.”
The new findings and immunotherapeutic strategies published in Cell Metabolism could 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 not able to make their own cellular energy, called adenosine triphosphate, or ATP, when they are inside a solid tumor.
In 2019, Thaxton’s lab studied T cells with optimal antitumor function. In a publication in Cancer Immunology Research, Hurst and Thaxton used a proteomics screen to identify enzymes associated with the optimal antitumor metabolism of these T cells. Through this screen, the duo found that ACC expression could limit the ability of T cells to make 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 may strike a balance between storing lipids versus breaking down those lipids and putting them into the citric acid cycle for energy,” Thaxton said. “If the ACC is turned ‘on’, cells normally store lipids. If the ACC is turned ‘off’, cells use the 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 several types of cancer. The observation, as well as other experiments, confirmed the team’s hypothesis that T cells were storing lipids rather than breaking them down.
Thaxton’s team then used CRISPR Cas9-mediated gene deletion to see what would happen if they “removed” ACC from the picture. The amount of lipid storage in the T cells was rapidly reduced, and the team was able to visualize fat being transferred to the mitochondria to generate energy.
Thaxton now hypothesizes that T cells may require a “delicate balance” of lipids to persist in solid tumors, in which a certain amount of lipid is devoted to cancer cell killing and a low level of fat is maintained in stores. Is kept.
The latest findings may prove useful in enhancing chimeric antigen receptor (CAR) T-cell therapy. This cutting-edge technology extracts T cells from cancer patients, modifies them in the laboratory to detect tumor cells, and then reinfects the cells to fight the patient’s cancer. Preliminary data from Thaxton’s laboratory show that manufactured T cells also contain additional lipid stores.
The lab is beginning to look at patient samples to understand how researchers could potentially flip the ACC metabolic switch directly in a patient’s tumor, eliminating the need to take the cells out and put them back into the body. But researchers must first determine how it might affect other immune cell populations in the body, such as macrophages.
