Immune cells called macrophages should function and protect, but cancer has found a way to get him to sleep. Now researchers at the University of Pennsylvania's Abramson Cancer Center say they have identified ways to refuel macrophages with the energy needed to attack and eat cancer cells. It is well known that macrophages can support the growth of cancer cells and spread or inhibit them. But most tumors also express a signal called CD47, which can put macrophages to sleep well and prevent them from eating. Researchers have found that the macrophage rewiring metabolism can overcome this signal and act like an alarm clock to generate and prepare macrophages to go to work. Their findings are published on Natural Immunology today.
Macrophages are immune cells like T and B cells, but are different because they can eat cells that are not supposed to be in the body. In fact, they are the most prominent immune cells found in cancer, but unfortunately, most are often convinced to help the cancer grow and spread. Cancer cells often stop macrophages from attacking them by expressing CD47, the signal "don't eat me". Researchers now say that only blocking blocking signals such as CD47 is not always enough to convince macrophages to attack cancer. Instead, two signals are needed. First, they need signals to activate it – like receptor agonists like tolls. After that, the second signal – like a CD47 inhibitor – can reduce the threshold needed to fight cancer.
"It turns out that macrophages need to be prepared before they can work, which explains why solid tumors can fight treatment with CD47 inhibitors," said the study's senior author Gregory L. Beatty, MD, PhD, assistant professor of Hematology. Oncology at the Perelman Penn Medical School. Jason Mingen Liu, an MD graduate student and PhD in Beatty lab, is the lead author of this study.
The team used this approach by activating macrophages with CpG, a toll-like receptor agonist that sent the first signal, and found that macrophages quickly induced tumor shrinkage and prolonged mouse survival even without T cell needs. Unexpectedly, they also found that activated macrophages were able eat cancer cells even in the presence of high CD47 levels.
To understand the molecular basis of this phenomenon, the team traced the metabolic activity of macrophages and determined that activated macrophages began using glutamine and glucose as fuel to support the energy needs needed for them to eat cancer cells. Changing the metabolism of this macrophage is needed so that CpG becomes effective, and the researchers say the findings show the importance of macrophage metabolism in determining the outcome of an immune response.
"Cancer does not shrink without the help of macrophages and macrophages need the right fuel to eat cancer cells and shrink tumors," Liu said. "To do this, a shift in metabolism is needed to direct energy in the right direction. It is this metabolism that ultimately allows the macrophages to override the signals that tell them not to do their jobs."
Beatty points out that patients with diabetes, cardiovascular disease, and other conditions are routinely treated with drugs that can affect the metabolism of macrophages, but almost nothing is known about how these drugs can affect immunotherapy responses to cancer, which means the team's findings have implications even for those who there is already treatment.
Material provided by University of Pennsylvania Medical School. Note: Content can be edited for style and length.