Ross Kedl and Jared Klarquist explain why new data on how some vaccines fuel the immune response could improve treatments for cancer and chronic disease. / Matthew Kaskavitch, University of Colorado Anschutz Medical Campus
Immune T cells produced in response to a vaccination package of viral fragments and immunity boosters rely on a different "fuel" than those produced by infection, a new study has revealed. The finding , published in the 7 September issue of Science Immunology, could guide the design of vaccines that fight harder against cancer and chronic infections.
"What we've found, and what this paper documents, is that the rules behind vaccination, and making T cells by vaccination, are considerably different than the rules that govern T cell responses to infections," said Ross Kedl, professor of immunology and microbiology at University of Colorado Denver, Anschutz Medical Campus and co-author of this study.
Based on their results, the researchers suggest further improvement of these viral fragment vaccines — called adjuvanted subunit vaccines — requires exploration of immune system processes distinct from those that are triggered when the body is infected with a whole pathogen.
"Knowing how the immune response is fueled after vaccination provides potential opportunities for metabolic or nutritional interventions for augmenting the response," said Kedl.
T cells play many critical roles in the immune system. Depending on the type of T cell, they can help other immune cells mature into their protective functions, keep wayward immune responses on a leash, develop memory of specific pathogens and directly kill invaders.
The earliest types of vaccines — for diseases like measles and polio, which are still used today — deliver weakened or dead viruses in their full forms. While these regimens are effective in stimulating a robust T cell immune response, they also increase the risk of adverse vaccine reactions.
More recently, scientists have developed vaccines that only contain subunits of the pathogen — harmless pieces of the viruses or bacteria that are sufficient targets for the body to formulate lasting immunity against the harmful invaders. These subunit vaccines, such as those for treating meningitis, hepatitis B, and some strains of influenza, for example, are typically applied with adjuvants, small doses of additives like aluminum salts or various oils that help kickstart the immune system's response to the vaccine.
"Adjuvanted subunit vaccines have transformed the way we vaccinate," said Kedl. "Unfortunately, the vast majority of adjuvants we have at our clinical disposal are extremely poor at generating T cell immunity, the arm of the immune system needed to fight something you already have, such as cancer, or a chronic infection like hepatitis C or HIV."
To formulate more effective adjuvanted subunit vaccines, scientists must find ways for these vaccines to elicit T cell responses on par with the powerful responses generated by the intact virus.
In mice, Kedl and his team closely investigated how T cells reacted to natural infection with Listeria bacteria, vaccinia virus, and influenza virus. They then examined how T cells responded after exposure to adjuvanted subunit vaccines, whereby the viral components delivered by the vaccine would jumpstart the immune cells' production of antibodies, proteins used to recognize and neutralize pathogens. The adjuvant would help the cells produce more antibodies and induce longer-lasting protection.
Kedl and his colleagues reasoned that studying T cell responses to adjuvanted subunit vaccines alone — allowing immunity to unfold without the additional inflammation generated during an actual infection — could provide valuable and novel insight into how T cells act during vaccination.
They found that cells exposed to adjuvants fuel their proliferations through metabolic processes based in mitochondria, the powerhouses of the cells. By contrast, T cells exposed to natural pathogens rely on the breakdown of glucose sugar to expand their numbers.
Researchers have assumed that robust T cell responses depend on glucose metabolism, but the new findings show that "the rules underpinning robust T cell immunity to an infectious agent compared to a vaccine adjuvant are actually quite different," Kedl explained.
One potential benefit of triggering cell division without glucose metabolism "is T cells with greater regenerative capacity are elicited, thereby promoting more durable or long-lasting immunity," said Steven Reiner, a professor of cancer research in microbiology and immunology at Columbia University Irving Medical Center, who is unaffiliated with this study.
The discovery has interesting implications for cancer immunotherapy, said Kedl and colleagues. Tumor cells are often in competition with the body's T cells for glucose. If T cells stimulated by adjuvanted vaccines don't use glucose for fuel and are generally indifferent to the sugar molecule, they may be "ideally suited to enhance currently existing immunotherapies against cancer, where the T cells can proceed with attacking the tumor instead of competing against the cancer for access to glucose," said Kedl.
Efforts to explore this possibility are already underway in Kedl's lab. "We are investigating exactly what fuels the elevated mitochondrial function in subunit vaccine-elicited T cells and all the necessary lipids, amino acids and nucleic acids required for their expansion," he said.
They are also exploring potential tumor therapies that combine adjuvanted subunit vaccination with inhibitors of glucose metabolism. They are examining how this combined regimen may influence cancer immunotherapies such as immune checkpoint blockade or chimeric antigen receptor (CAR) T cell therapies.
[Credit for associated image: ps_sahana/ Flickr]