Creatine, the organic acid commonly used by athletes and bodybuilders as a dietary supplement, is a molecular battery for immune cells, according to new UCLA research, by storing and distributing energy to strengthen their fight against cancer.
A study carried out on mice and published in the Journal of Experimental Medicine is the first to show that creatine uptake for the antitumor activity of CD8 T cells, also known as killer T cells, the foot soldiers of the Immune system, is crucial. Researchers also found that creatine supplementation can improve the effectiveness of existing immunotherapy.
"Since oral creatine supplements have been used extensively by bodybuilders and athletes over the past three decades, the data available suggests that they are likely to be safe if taken at appropriate doses," said Lili Yang, a member the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at UCLA and the lead author of the study. "This could provide a clear and convenient way to use creatine supplementation to enhance existing cancer immunotherapies."
The paper's findings are from the Yang Laboratory's research on the metabolic needs of tumor infiltrating lymphocytes, immune cells that travel into tumors to fight cancer. Examining these cells, the team found that killer T cells taken within tumors had a large number of creatine transporter molecules sitting on the cell surfaces and controlling creatine uptake into cells.
why? "Said Yang, who is also Assistant Professor of Microbiology, Immunology and Molecular Genetics and a member of the UCLA Jonsson Comprehensive Cancer Center . "We've found that these T-cells have increased their capacity to absorb creatine, probably for good reason, so we've developed experiments to see what happens if they do not get it."
The lab was genetically engineered mouse models, so their killer T cells lacked a gene called CrT, or Slc6a8 which is responsible for the production of creatine transporter molecules. They found that mice whose killer T cells could not take creatine were less able to fight tumors.
The team then reviewed their hypothesis from the opposite point of view and gave non-genetically engineered mice a daily dose of creatine comparable to the safe dose recommended for athletes and bodybuilders. This creatine boost ̵
creatine for the fight against cancer, "said Yang. "Without them, they simply can not do their job effectively."
Creatine occurs naturally in humans and other vertebrates. It is mainly produced in the liver and kidneys. Most people consume extra creatine via their diet, with meat and fish the main sources. In addition to these natural sources, creatine supplements are widely used by athletes and bodybuilders who want to build muscle mass and improve performance.
The popularity of creatine supplements is based on the knowledge that high-energy cells, such as those found in muscles, are very popular and brain tissues use creatine to store excess energy when they are most needed.
These new findings extend the list of creatine-dependent cells to killer T cells, which all use two different energy sources, much like hybrid cars. The first source of energy is a metabolic process that resembles a fuel engine and converts nutrients such as glucose, amino acids and lipids into ATP, the energy cell of cells. The secondary energy source is creatine, which – like the battery of a hybrid car – absorbs excess energy (in this case ATP) and stores it for release when fuel runs short, allowing the cells to continue working until more fuel can be burned.  "With this creatine-driven hybrid motor system, killer T cells can best utilize their available energy supply in an environment where they need to compete for nutrients with fast-growing tumor cells," said Yang.
The team has attempted to combine creatine supplementation with PD-1 / PD-L1 blockade therapy, a form of cancer immunotherapy that prevents the depletion of T cells from cervix. They found that creatine supplementation and anti-PD-1 blockade therapy worked synergistically and tipped the metabolic scales in favor of T cells, allowing them to avoid fatigue and effectively fight cancer over a longer period of time.
Four out of five mice receiving this combination therapy were found to have completely eradicated their colon cancer tumors and remained tumor free for three months. In a second round of tumor cells, all of these "cancer survivors" mice were protected from tumor recurrence and remained tumor free for a further six months.
As a next step, the team repeats these experiments with special mouse models that harbor human tumor transplants and human immune cells. If they are able to reproduce these effects in human cells, the team will work to determine the right dose, the right time, and the right method to give people creatine supplements to improve existing immunotherapies. Since the strategy has proven to be effective in both melanoma and colorectal cancer mouse models, the team estimates that the results could be valid for a range of cancers.
The experimental combination therapy described above was only used in preclinical tests and in non-tested human or by the Food and Drug Administration as safe and effective for human use. This newly identified therapeutic strategy is covered by a patent application filed by the UCLA Technology Development Group on behalf of the Regents of the University of California with Yang and Stefano Di Biase as co-inventors.
The researchers recommend a: A doctor who incorporates a new supplement such as creatine into their routine, as supplements may pose the risk of drug interactions and other harmful side effects. There is concern that the long-term use of high-dose creatine could damage the liver, kidneys or heart.
The study was funded by the National Institutes of Health, a UCLA Tumor Immunology Training Grant and the Stem Cell Training Program of the UCLA Broad Stem Cell Research Center.