



Glucose is typically the primary fuel source for the vast majority of the body’s cells. Moreover, when cells are under stress, they will switch from using glucose and scavenge other sources to maintain energy reserves—often extremely inefficiently. However, a new finding surrounding how vaccine-induced T cells utilize glucose from investigators at the University of Colorado Anschutz Medical Campus could have major implications for the development of immunotherapies for cancer patients. Results from the new study were published recently in Science Immunology through an article entitled “Clonal expansion of vaccine-elicited T cells is independent of aerobic glycolysis.”

In the current study, the research team discovered that disease-fighting T cells, elicited from vaccines, do not require glucose for their rapid reproduction. The scientists examined T cells that arose in the body's immune system after they received a subunit vaccination—a vaccine that uses just part of a disease-causing virus. Additionally, the researchers found that these critical white blood cells, which attack and kill the infection, did not rely on glucose to fuel their rapid division which occurs every two to four hours. Instead, they used another cellular engine, the mitochondria, to support their expansion.

“The knowledge that this magnitude of cell division can be supported by mitochondrial function has a number of potential practical implications for the development of future vaccines,” explained senior study investigator Ross Kedl, Ph.D., professor of immunology and microbiology at the University of Colorado School of Medicine.

T cells responding to infection usually depend on glucose for fuel—as do cancerous tumors. When T cells come up against tumors, they end up competing for glucose and the T cells often lose. Yet, when a T cell doesn't need glucose, it has a better chance of defeating tumor cells.

“T cells generated by subunit vaccination are ideally suited for use against cancer in conjunction with drugs that block aerobic glycolysis, a metabolic pathway to which the cancer is addicted,” Dr. Kedl noted. “Tumor growth can be inhibited while the T cells are free to attack the tumor instead of competing against it for access to glucose.”

Scientists have historically studied T-cell responses to infection with the idea that if they could understand how the cells respond, they could create better vaccines. Interestingly, Dr. Kedl and his colleagues had already discovered a noninfectious vaccine method that could induce the same level of T-cell immunity as those using infection. Since then, researchers have found that the rules governing T-cell responses to an infectious agent are very different from the cell's response to a subunit vaccine. And now, the fact that T cells derived from subunit vaccines don't require glucose to reproduce is a major finding.

“Prior to these findings, it was generally thought that whereas the mitochondria are good at making energy, T cells need glucose to produce the raw materials like proteins, fats and nucleic acids (like DNA) required to turn one cell into two,” commented lead study investigator Jared Klarquist, Ph.D., a postdoctoral scientist in Dr. Kedl’s laboratory. “Knowing how the immune response is fueled after vaccination provides potential opportunities for metabolic or nutritional interventions for boosting a vaccine-elicited immune response.”

Dr. Kedl agreed, concluding that “perhaps most intriguing, however, is the application of this knowledge to cancer immunotherapy.” The lab is currently exploring how these strategies might positively influence the outcomes of immune-based cancer treatments that are already in the clinic.



























