Biochemist and bioengineer Dr. Kayvan Keshari says immune cells reprogrammed to use fructose as fuel could potentially become “super soldiers” that fight cancer.
Immune cells might be reprogrammed to use the body’s fructose — a naturally occurring sugar — as an energy source that supercharges them to fight cancer, researchers at Memorial Sloan Kettering Cancer Center (MSK) have found. The engineered immune cells showed strong anti-tumor effects in mouse models. The finding suggests the potential for enabling cells to use the body’s ample fructose as “jet fuel” to increase their power.
Taking Advantage of Abundant Fructose in Tumor Microenvironment
The retooled cells could metabolize fructose in the tumor microenvironment — the noncancerous cells, tissues, and blood vessels that surround a tumor. The tumor microenvironment is generally a hostile place for immune cells, dampening their function after they flock there to attack the cancer. T cells engineered to exploit fructose in that same environment could gain a huge boost in fighting the tumor.
“T cells that take advantage of this abundant resource could act as a powerful mobile army at the tumor site,” says MSK biochemist and bioengineer Kayvan R. Keshari, PhD, who led the research. The study is reported in the journal Cancer Cell by Dr. Keshari’s team, which includes co-first authors Tanya Schild, PhD, and Patrick Wallisch, MSc, and second author Yixuan (Skye) Zhao, BS, a student in the GSK Graduate School of Biomedical Sciences.
Fructose as a Neglected Cancer-Fighting Fuel Source for Immune Cells
In recent years, understanding the way cancer cells metabolize sugar has become an intense area of study, especially at MSK. Different types of sugar perform different functions:
- Sucrose starts in the body and is then broken down into glucose and fructose.
- Glucose fuels most cells in the body and is tightly regulated. More than normal cells, cancer cells rely on glucose. They hog the glucose in the microenvironment, starving immune cells who depend on the nutrient to multiply and attack the cancer.
- Fructose is typically consumed by the liver and intestine and converted to glucose. In most cases, it’s not directly processed by cancer cells or normal cells. Because of this lack of direct use by most cells in the body, fructose has largely been discounted by cancer researchers.
“Fructose it is abundant all over the body, and we obviously develop cancers in all those places,” Dr. Keshari says. “We wondered if we could engineer immune cells to efficiently use this other nutrient. Could we give them a metabolic ability they are not supposed to have and turn them into super soldiers?”
GLUT5 Protein Enhances Fructose Metabolism
In recent years, Dr. Keshari’s lab has taken a closer look at how cells interact with fructose. They found that in rare cases, cancer cells can switch to a different metabolic pathway to use fructose as an alternative fuel source when glucose levels are low and fructose is plentiful. The cancer cells use a protein called GLUT5 to usher the fructose into the cells and metabolize it as quickly as if it were glucose.
The researchers wondered if they could program immune cells to express high levels of GLUT5 to boost their effectiveness. The researchers engineered various types of immune cells to boost GLUT5 expression and tested their performance in a lab dish as well as in mouse models. All types showed higher effectiveness against tumors — which additionally increased when the researchers added fructose to the environment.
“We can manipulate this system we have engineered,” Dr. Keshari says. “When we put the mice on a high-fructose diet, their immune cells kill the tumor even more effectively.”
Making Cells More Fit to Run on Fructose and Kill Tumors Cells
Dr. Keshari adds that the potential application goes beyond just immune cells. His lab’s research suggests that almost any cell in the body can be made “more fit” by engineering them to metabolize fructose when glucose levels are low.
“It looks like a general phenomenon, which opens up many possibilities,” Dr. Keshari says. “You might be able to do this with stem cells and put them into tissues that you want to regenerate, such as cartilage tissue, to improve wound healing.”
He explains that engineering cells offers advantages over more conventional ways of manipulating metabolism.
“What most people do is characterize some process and then try to make a drug to inhibit the protein involved,” he says. “The problem is that cells can adapt and express something else to try to carry out their normal function. We are approaching this from a different angle — making the cells do something positive that they will not try to adapt away from.”
His team is trying to further refine the cell engineering process to improve their potential.
“If we think about a cell as an engine that runs a certain way, can we manipulate all the parts to optimize it?” he says. “Maybe we can make it independent of signals that would turn it on or off, or make it respond to external signals that we can control. It’s exciting to think of how to use the latest cell engineering tools to tinker with this to make it even more effective and safe.”
