Macrophages are immune cells just like T and B cells, but they differ in that they can eat cells that are not supposed to be in the body, such as cancer cells. But most tumors express a signal called CD47, which can lull macrophages into a deep sleep and prevent them from eating. Researchers at Penn’s Abramson Cancer Center have found that rewiring macrophage metabolism can overcome this signal and act like an alarm clock to rouse and prepare macrophages to go to work. Their findings were published in Nature Immunology.

To convince macrophages to attack cancer, the researchers note that first they need a signal to activate them, such as a toll-like receptor agonist. After that, a second signal, such as a CD47 inhibitor, can lower the threshold needed to wage battle on the cancer.

“It turns out macrophages need to be primed before they can go to work, which explains why solid tumors may resist treatment with CD47 inhibitors alone,” said the study’s senior author Gregory L. Beatty, assistant professor of hematology-oncology at Penn’s Perelman School of Medicine. Jason Mingen Liu, PhD graduate student in Dr. Beatty’s lab, is the study’s lead author. Collaborators include Nathaniel Snyder, assistant professor at Drexel University, and Roddy O’Connor, research assistant professor in pathology and laboratory medicine at Penn.

The team used this approach by activating macrophages with CpG, a toll-like receptor agonist that sends the first signal, and found that it rapidly induced shrinkage of tumors and prolonged survival of mice even without the requirement of T cells. They found that the activated macrophages were able to eat cancer cells even in the presence of high levels of CD47.

The team determined that activated macrophages began to utilize both glutamine and glucose as fuel to support the energy requirements needed for them to eat cancer cells. This rewiring of the macrophages metabolism was necessary for CpG to be effective, and the researchers say these findings point to the importance of macrophage metabolism in determining the outcome of an immune response.

Dr. Beatty pointed out that patients with diabetes, cardiovascular disease, and other conditions are routinely treated with drugs that could affect macrophage metabolism, but virtually nothing is known about how these drugs might impact immunotherapy responses in cancer, meaning the team’s discovery has implications even for existing treatments.