A group of researchers from the Abramson Cancer Center of the University of Pennsylvania have recently found an interesting way to trigger macrophages to target cancer cells. Though cancer cells typically possess traits that signal the immune system not to destroy them, these researchers found that activating macrophages in a certain manner allows them to bypass these traits and destroy the cancerous cells.
Macrophages are a type of white blood cell that function to engulf and destroy pathogens and other entities the immune system must clear. What makes most tumor cells resistant to this immune mechanism is that they express CD47, a surface protein that signals macrophages not to destroy cells possessing it. The protein is typically found on many cells in the body, being that it would be detrimental if macrophages blindly attacked every cell they encountered, but cancer cells having this protein allows them to be undetected by macrophages.
In this study, researchers found that altering macrophage metabolism can allow these cells to overcome the CD47 protein on cancer cells and successfully attack them. Their work was published in Nature Immunology.
Researchers claim that simply blocking inhibitory mechanisms such as CD47 are not a sufficient means of triggering macrophages to attack tumors. What is instead necessary is use of two signals, one to activate the macrophages, and a second to inhibit signals such as CD47.
“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 Gregory L. Beatty, senior author and assistant professor of Hematology-Oncology at Penn’s Perelman School of Medicine. The study’s lead author was Jason Mingen Liu, MD/PhD graduate student in Beatty’s lab.
Beatty’s team employed this approach by activating macrophages with CpG, a receptor agonist that administers the first signal, and observed rapid reduction in tumor size and increase in survival of mice in the study. Additionally, the team found that these effects occurred without requirement of T cells. Surprisingly, the researchers noted that these activated macrophages engulfed cancer cells even when CD47 was present in high quantities.
To better understand this mechanism at the molecular level, the researchers tracked the macrophages metabolic activity to find that they were using glutamine and glucose as an energy source for phagocytosis. This alteration in macrophage metabolism was needed for CpG to work effectively, and the researchers claim this highlights the importance of macrophage metabolism in effective immune responses.
“Cancer does not shrink without the help of macrophages and macrophages need the right fuel to eat cancer cells and shrink tumors,” said Liu. “To do this, a shift in metabolism is needed to steer the energy in the right direction. It is the metabolism that ultimately allows macrophages to override signals telling them not to do their job.”
Beatty noted that patients with cardiovascular disease, diabetes, and several other conditions are often treated with drugs affecting macrophage metabolism, despite the lack of evidence as to how these drugs affect cancer therapies. He feels this emphasizes that his team’s findings have implications for existing treatments as well.
This research was funded by the National Institutes of Health and the Seed Grant Program from the American Medical Association Foundation. Other study collaborators include Nathaniel Snyder, assistant professor at Drexel University, and Roddy O’Connor, PhD, and research assistant professor in Pathology and Laboratory Medicine at Penn.
Metabolic rewiring of macrophages by CpG potentiates clearance of cancer cells and overcomes tumorexpressed CD47mediated ‘don’teatme’ signal.: Macrophages enforce antitumor immunity by engulfing and killing tumor cells. Although these functions are… https://t.co/cgZwD9AGyL
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