PHILADELPHIA - After a vaccination or an infection, the human immune system remembers to keep protecting against invaders it has already encountered, with the aid of specialized B-cells and T-cells. Immunological memory has long been the subject of intense study, but the underlying cellular mechanisms regulating the generation and persistence of long-lived memory T cells remain largely undefined. Now, University of Pennsylvania School of Medicine researchers have found that a common anti-diabetic drug might enhance the effectiveness of vaccines. The findings are described this week in an advanced online publication of Nature.
In this study, an experimental preventive vaccine was made more efficacious by boosting numbers of cancer fighting T cells with the anti-diabetic drug metformin. This resulted in a larger population of memory immune cells that were able to fight off a tumor at a later time.
"We serendipitously discovered that the metabolizing, or burning, of fatty acids by T cells following the peak of infection is critical to establishing memory in those T cells," says senior author Yongwon Choi, PhD, Professor of Pathology and Laboratory Medicine. "As a consequence, we used the widely prescribed anti-diabetic drug metformin, which is known to operate on fatty-acid metabolism, to enhance this process."
"We have shown experimentally in mice that metformin increases T-cell memory as well as the ensuing protective immunity of an experimental anti-cancer vaccine," notes postdoctoral fellow and first author Erika Pearce, PhD.
"These findings were unanticipated, but are potentially extremely important and could revolutionize current strategies for both therapeutic and prophylactic vaccines," says Choi.
The lab developed mice deficient in TRAF6, a protein important in the immune response. They found that CD8 T cells deficient in TRAF6 mount an initial response, meaning they are able to proliferate into an army of so-called effector cells that can clear infection. However, TRAF6-deficient CD8 T cells do not develop into a population of memory cells that can recall a particular infectious agent when the body encounters it a second time.
Using microarray analysis and a program that searches protein pathways, the team compared the gene expression profiles of TRAF6-deficient cells and cells with TRAF6 to see what stood out. "We discovered differences in genes that regulate fatty acid metabolism," says Pearce. Fatty acids can be broken down for energy and the microarray analyses revealed that TRAF6-deficient CD8 T cells exhibit altered expression of genes that regulate this process.
Consistent with the microarray findings, CD8 T cells lacking TRAF6 display defective fatty acid oxidation in response to growth factor withdrawal. Giving the mutant mice the metformin restored fatty acid oxidation and the generation of memory cells that lack TRAF6. Remarkably, this treatment also increased the generation of memory cells in normal mice, and consequently was able to significantly improve the efficacy of an experimental anti-cancer vaccine. A lack of fatty acid metabolism is correlated with lack of T-cell memory and through in vitro studies the team also saw that T cells burn more fatty acids when given metformin.
T cells proliferating to form an army of effector cells burn glucose for their energy. Non-proliferating T cells, such as memory cells, burn fatty acids, amino acids, and glucose interchangeably in a different metabolic pathway. From this, explains Pearce, "it is implied that there's a switch in metabolism somewhere along the way between proliferating and non-proliferating T cell populations." Perhaps at the peak of the proliferation, when energy is limiting and cells are metabolically stressed, there is a switch to another energy pathway to survive, say from glucose to fatty acids.
"Most T cell vaccines have a good initial response, but the development of long-term T memory cells has been difficult to achieve," says Choi. "The key improvement we're hoping to contribute is to use the traditional vaccine, then with the proper timing, we can use metformin, in theory, to boost the development of memory cells. We want to enhance immunity after an initial vaccination so we can make vaccines that are being tested now better."
This work was funded in part by grants from the National Cancer Institute and the Canadian Institutes of Health Research. Co-authors in addition to Choi and Pearce are Matthew C. Walsh, Pedro J. Cejas, Gretchen M. Harms, Hao Shen, and Li-San Wang, all from Penn as well as Russell G. Jones from McGill University, Montreal.
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