T cells, often celebrated as the assassins or killers of the immune system, are critical for targeting and eradicating various threats like bacteria, viruses, and cancer cells. Despite their potent capabilities, recent research has unveiled a concerning phenomenon – when T cells penetrate solid tumor environments, they lose the essential energy required to combat cancer effectively. Led by Jessica Thaxton, Ph.D., MsCR, an associate professor at UNC Lineberger Comprehensive Cancer Center, a research team delved into the underlying reasons for T cell energy depletion in tumors.
Drawing on their expertise in tumor immunity and metabolism, Thaxton’s team, spearheaded by Katie Hurst, MPH, and graduate student Ellie Hunt, identified a metabolic enzyme known as Acetyl-CoA Carboxylase (ACC) as a key player in diverting T cells’ focus towards fat storage rather than utilizing it for energy production.
Thaxton expressed, “Our discovery addresses a longstanding gap in understanding why T cells fail to sustain their energy levels within solid tumors.” In mouse cancer models where ACC expression was inhibited, T cells exhibited enhanced persistence within tumors, indicating the potential for improved effectiveness of T-cell therapies.
The team’s findings, detailed in Cell Metabolism, offer promising insights for refining various T-cell therapies, including checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell treatments. Previous research had highlighted the challenge of T cells failing to generate adequate cellular energy (adenosine triphosphate or ATP) while situated within solid tumors.
In an earlier study published in Cancer Immunology Research, Hurst and Thaxton had identified enzymes associated with optimal antitumor metabolism in T cells and uncovered a link between ACC expression and ATP production limitation within tumors. By regulating lipid breakdown, ACC acts as a crucial modulator, influencing whether cells store or utilize fats for energy generation.
Thaxton elucidated, “Acetyl-CoA carboxylase essentially dictates the balance between lipid storage and breakdown, impacting cellular ATP production.” Imaging analyses by Hunt confirmed T cells’ propensity for lipid accumulation rather than breakdown in cancer settings.
Utilizing CRISPR Cas9-mediated gene editing, the team observed a rapid decrease in lipid storage upon ACC deletion, with fats relocating to mitochondria for energy synthesis. Thaxton suggested a nuanced lipid balance within T cells to sustain tumor persistence, allocating lipids for cancer cell elimination while maintaining minimal fat stores.
Notably, the research could enhance CAR T-cell therapies, a cutting-edge approach involving modification of patient T cells outside the body to target and fight cancer cells. Initial indications from Thaxton’s lab revealed surplus lipid stores in engineered T cells, prompting further exploration into direct manipulation of the ACC metabolic switch within patient tumors.
Future investigations aim to decipher the impact on other immune cell populations like macrophages before implementing strategies to modulate lipid metabolism within tumors. By unraveling the metabolic complexities influencing T-cell function in solid tumors, this research opens new avenues for refining immunotherapies and advancing cancer treatment paradigms.
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1. Source: Coherent Market Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it.
