Feed macrophages with energy to attack and eat cancer cells

The immune cells called macrophages are supposed to serve and protect, but the cancer has found ways to put them to sleep. Researchers at the Abramson Cancer Center of the University of Pennsylvania now claim to have discovered how to fuel macrophages with the energy needed to attack and eat cancer cells. It is well established that macrophages can promote the growth and spread of cancer cells or hinder it. But most tumors also express a signal called CD47, which can make macrophages sleep and prevent them from eating. The researchers found that rewiring macrophage metabolism can overcome this signal and act as an awakening to wake up and prepare macrophages at work. Their findings were published in Nature Immunology today.

Macrophages are immune cells in the same way as T and B cells, but they differentiate in that they can eat cells that are not supposed to be found in the body. In fact, they are the most common immune cell in cancer, but unfortunately most are often convinced to help cancer to develop and spread. Cancer cells often prevent macrophages from attacking them by expressing CD47, a signal "do not eat me". Researchers now say that simply blocking inhibitory signals such as CD47 is not always enough to convince macrophages to attack cancer. Instead, two signals are needed. First, they need a signal to activate them, such as a receiver agonist similar to a toll. After that, a second signal – such as a CD47 inhibitor – can lower the threshold needed to fight cancer.

"It turns out that macrophages need to be prepared before they can work, which is why solid tumors can resist treatment with only CD47 inhibitors," said the lead author of the study. study, Gregory L. Beatty, MD, PhD, badistant professor in hematology. Oncology at Penn's Perelman School of Medicine. Jason Mingen Liu, a doctoral student in Medicine and PhD at Beatty's lab, is the lead author of the study.

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 induces tumor shrinkage and prolonged mouse survival, even without resorting to Unexpectedly, they also found that activated macrophages were able to eat cancer cells even in the presence of high levels of CD47.

To understand the molecular basis of this phenomenon, the team traced the metabolic activity of macrophages and determined that activated macrophages were beginning to use glutamine and glucose as fuel to meet the energy requirements needed for consumption of cancer cells. This rewiring of macrophage metabolism was necessary for CpG to be effective, and the researchers explain that these results underscore the importance of macrophage metabolism in determining the outcome of an immune response.

"Cancer does not go back without the help of macrophages and macrophages need the right fuel to eat cancer cells and reduce tumors," Liu said. "To do this, a metabolic shift is needed to direct the energy in the right direction.This is the metabolism that ultimately allows macrophages to override signals telling them not to do their job."

Beatty points out that patients with diabetes, cardiovascular disease and other conditions are routinely treated with drugs that may affect macrophage metabolism. However, virtually nothing is known about the effect of these drugs on immunotherapeutic responses to cancers. treatments.