Kyoto, Japan -- While modern life includes many conveniences, humans are still incessantly exposed to a variety of metabolic stresses we have never experienced before. Our immune systems are constantly trying to protect us, and CD8⁺ T cells in particular -- also known as killer T cells -- play an essential role in attacking tumors.
A team of researchers from Kyoto University's Center for Cancer Immunotherapy and Immunobiology, CCII, and the RIKEN Center for Integrative Medical Sciences was motivated to investigate how metabolic stress can persist in the immune system and its consequences, particularly on anti-tumor immunity.
"Since each one of us experiences variable types of stress throughout our lives, we were interested in finding where and how that stress may influence our health," says first author Masaki Tajima of CCII.
The research team used three groups of mice for their study. One group was put on a high fat diet for twelve weeks, another group received a normal diet also for twelve weeks, and the final group was fed a high fat diet for six weeks, followed by a normal diet for the remaining six weeks. The researchers then injected the mice with tumor cells and analyzed their immune systems to evaluate the impact of the different diets on the mice's ability to fight tumors.
The results revealed that exposure to a high fat diet, even for a short time, induced metabolic stress that persisted long after returning to a normal diet. Specifically, it caused lasting changes to the fatty acid composition in killer T cells, making them susceptible to ferroptosis, a form of cell death, and thus affecting the immune system's tumor-killing function. The researchers call these persistent changes a metabolic tattoo.
However, the team also found a pathway to protecting killer T cells. They were surprised to discover that the cells salvage xanthine -- an end product of purine metabolism -- when under oxidative stress within tumors. The killer T cells recycle xanthine to produce GTP, which they then use to produce BH4, a powerful antioxidant that helps fuel the killer T cells. This effectively boosts the pool of antioxidants, improving their ability to withstand the harsh oxidative stress encountered in the tumor microenvironment.
While this study shows how past experiences of metabolic stress can persist in our immune systems, it also uncovers a pathway to 'removing' this metabolic tattoo by fueling killer T cells through purine metabolism. These findings have the potential to improve the efficacy of immunotherapy in certain patients.
Next, the researchers are curious to find new applications for activating purine metabolism to support killer T cells' ability to fight cancer and viral infections. They would also like to identify the critical lipid species that induce killer T cells' vulnerability to ferroptosis, and those that assist in activation.
