Sugar helps cancer grow, but the immune system also uses sugar to help its cells grow and divide. What happens to the effectiveness of immunotherapy when there’s a competition with cancer cells over sugar? Researchers behind a new study aimed to find out.
Combining mouse models and data from cancer patients, Memorial Sloan Kettering Cancer Center researchers found that the more sugar a tumor consumed, the less effective immunotherapy became. These results were published February 15th in the journal Nature.
Dr. Taha Merghoub, a co-leader on the study, says, “If we reduce a tumor’s use of glucose, then we free up more of it for immune cells to use, which benefits the immune response.”
Researchers say this may serve as a way to improve checkpoint blockade immunotherapy. Immune checkpoints prevent immune system responses that are so strong they destroy healthy cells. They engage when checkpoint proteins on the surface of immune cells called T cells recognize and bind to partner proteins on other cells, including those on tumors.
Once these two proteins bind together, an off signal is sent to the T-cells, which can stop the immune system from destroying tumors. Immune checkpoint inhibitors block checkpoint proteins from binding to partner proteins, which stops the off signal from being sent and allows the immune system to kill cancer cells.
The researchers used this treatment alongside a mouse model of breast cancer that uses a lot of sugar to grow. In one group of tumors, they knocked down a key enzyme used by cells to rapidly consume glucose, in a process known as glycolysis. In the other group, they left the enzyme alone. The mice were treated with checkpoint inhibitors that targeted the checkpoint protein CTLA-4 before having surgery to remove the tumor.
Researchers found that the mice with tumors that consumed less sugar lived longer and were less apt to have their cancer spread. In addition, it seemed that the immune system could remember this response. When tumors were re-implanted in mice that had already had exposure to the less glycolytic tumors, the tumor growth was still stunted. In mice from the other group, the tumor growth continued.
Researchers also compared glucose use by tumors in humans to the number of immune cells present in a tumor. They found that the more glucose was used, the fewer immune cells there were.
The study authors say there are two types of T cells important to immune checkpoints – effector T and regulatory T cells, or Tregs. Effector T cells kill cancer cells, and Tregs work as a brake on the effector T cells. They respond to glucose differently. More glucose allows the effector T cells to kill more cancer, while Tregs lose their ability to slow down the attack with more glucose. This means that allowing more glucose to be used by the immune system can pack a double punch for cancer.
Dr. Roberta Zappasodi, who teaches at Weill Cornell Medicine and took part in the research, says, “It was surprising and exciting to see that CTLA-4 blockade induces Tregs to use glucose and that this in turn reduces the suppression activity of these cells.”
Dr. Merghoub adds, “The implication is that for tumors that are highly glycolytic and don’t respond to immune checkpoint blockade, one way of overcoming this resistance is to target tumor glycolysis with drugs.”
There are challenges in making this happen, though. The study authors say existing drugs that block sugar use by cancer cells also block its use by immune cells. They are now looking into ways to prevent tumor cells from using glucose while letting the immune system use it freely.