When cancer cells and immune T-cells compete for glucose, more commonly known as sugar, cancer cells will win, according to new University research. According to the study, which was released Tuesday, the competition results in unhealthy immune system T-cells that are unable to fight the cancer.
Conducted by researchers from the University’s Medical School, the study focused on the human cancer microenvironment, which holds the key to understanding the immune system’s response to cancerous tumors and the patient’s response to therapy.
Immunotherapy, a type of therapy that has been researched extensively in recent years and aims to employ the body’s immune system to fight off some cancers, was a focus of the research led by Weiping Zou, the University’s Charles B. de Nancrede professor of surgery, immunology and biology and the director of translational research.
Zou said the fields in which the study was based — tumor biology and immunotherapy — are difficult to work in because only a fraction of patients respond to the treatment and the likelihood of response varies based on a patient’s existing T-cell count.
“T-cells are the soldiers in the immune system,” Zou said. “The T-cells kill the tumors, so the T-cells are important. But the T-cells must be in the tumor microenvironment, and the T-cells must be also functional in the tumor microenvironment. That’s the problem we have been working on for many years.”
Zou said the tumor microenvironment and the tumor itself may affect the T-cells because they all share the same microenvironment.
“What we saw is that it turns out the T-cells and the tumor cells are actually competing for glucose in the microenvironment,” Zou said. “The T-cells are not able to compete efficiently with the tumor cells because the tumor cells … could be resistant to the harsh environment. Therefore, this hurts the T-cells. The T-cells are not able to be fully functional, and they are not able to kill the tumor in an efficient manner.”
According to Zou, the study ultimately concluded that current immunotherapy clinical trials with PD-L1 and PD-1 blockade, which are immunotherapy-based inhibitors, indicate that tumors with a high number of T-cells were more responsive to these immunotherapy-based inhibitors than tumors with a lower number of T-cells.
Though tumor cells are killed during chemotherapy and radiation therapy, a number of healthy cells are also killed, Zou said. However, in the case of immunotherapy, the tumor cells are selectively killed, rather than employing a treatment that could also potentially damage cells in the rest of the body, as is common in chemotherapy.
Additionally, the side effects of immunotherapy are more manageable and quite minimal. Some patients could be cured of cancer, and others will have a long-term positive response.
“If the patient is not responsive, it means they have very few T-cells in the tumor,” Zou said. “And even if they have T-cells, the T-cells may not be functional. One reason may be they don’t have sufficient sugar because of the competition between tumor and T-cells. So in that case, we have two ways to reprogram it.”
The first is to reprogram the T-cells to ensure they move into the tumor. Once they’re inside, the second aim is to make sure they are resistant to the harsh tumor environment.
According to Zou, while researchers might not be able to fix the problem immediately, they hope the new knowledge may help drive the search for a solution. Educational institutions and many pharmaceutical companies are now working on finding methods to reprogram the T-cells, and the research continues to evolve.
“The strategy right now is combination,” Zou said. “That means you use different ways, you combine them together. For example, we know now that the PD-1 blockade could work. But for some patients, we don’t see T-cells … So before we do this therapy, we can do something else, to increase the T-cells in the tumor.”
Zou said much of what he and his colleagues discuss is why some patients are responsive and some other are not.
Pavan Reddy, professor of translational oncology and internal medicine, works as a tumor immunologist and physician scientist at the University familiar with this type of research.
“The ability to manipulate the immune system to get rid of cancer is now one of the most exciting methods of therapy available,” Reddy said.
T-cells are probably among the most critical immune cells in the body, specifically for eliminating tumor cells, Reddy said. However, because not all T-cells survive and not all are very functional in the tumor environment, the paper published by Zou and his co-authors provides fundamental insight into potential methods to allow the T-cells to become functional to kill the cancer cells.
“Tumor cells use glucose in a unique manner compared to normal tissues,” Reddy said.
Reddy said the research shows a surprising but important connection between the T-cells and their competition with cancer cells for glucose. He also agreed with Zou, saying the use of immunotherapy could present a much more precise treatment compared to other approaches like chemotherapy.
Because it would be difficult and impractical to collect data on all types of cancers, Reddy said, the recent research was done specifically with human melanoma and ovarian cancer samples. However, he said the research is likely applicable to many other kinds of cancers as well.