Energizing the immune system to eat cancer

PHILADELPHIA – Immune cells called macrophages are supposed to protect and protect you. Now researchers at the Abramson Cancer Center of the University of Pennsylvania say they've identified fuel cells with macrophages and cancer cells. It is well established that macrophages can support cancer cell growth and spread or hinder it. But most tumors also express a signal called CD47, which can lull macrophages into a deep sleep and prevent them from eating. Researchers 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 have been published in Nature Immunology today.

Macrophages are immune cells just like cells and they are not immune to the body. In fact, they are the most prominent immune cells found in cancer, but unfortunately, they are most often convinced to help cancer grow and spread. Cancer cells frequently stop macrophages from attacking them by expressing CD47, a "do not eat me" signal. Researchers now say that they are simply blocking inhibitory signals like CD47 is not necessarily enough to convince macrophages to attack cancer. Instead, two signals are required. 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 war on cancer.

"It turns out macrophages need to be primed before they can go to work, which explains why solid tumors may be resistant to CD47 inhibitors alone," said the senior study author Gregory L. Beatty, MD, PhD, an badistant professor of Hematology- Oncology at Penn's Perelman School of Medicine. Jason Mingen Liu, an MD and PhD graduate student in Beatty's lab, is the study's lead author.

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 tumors and prolonged survival of mice even with the requirement of T cells. 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 to utilize both glutamine and glucose as fuel to support the energy requirements. This rewiring of the macrophages is necessary for the efficacy 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, it is possible that the metabolism causes that macrophages to override the signals to their job."

Beatty points out that patients with diabetes, cardiovascular disease, and other conditions are routinely treated with drugs that may affect macrophage metabolism. treatments.

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Collaborators on this study include Nathaniel Snyder, an badistant professor at Drexel University, and Roddy O'Connor, PhD, a research badistant professor in Pathology and Laboratory Medicine at Penn.

This research is supported by the National Institutes of Health (R01 CA197916, R03 HD092630, F30 CA196124) and the Seed Grant Program from the American Medical Association Foundation.

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