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Anti-tumor antibodies could counter atherosclerosis, Stanford study finds

Investigators at the Stanford University School of Medicine have learned the signal that tumor cells display on their surfaces to protect themselves from being devoured by the immune system also plays a role in enabling atherosclerosis, the process underlying heart attacks and strokes.

A biological drug capable of blocking this so-called “don’t eat me” signal is now being tested in clinical trials in cancer patients. The same agent, the investigators found, was able to prevent the buildup of atherosclerotic plaque in several mouse models of cardiovascular disease. If this success is borne out in human studies, the drug could be used to combat cardiovascular disease – the world’s No. 1 killer – and do so by targeting not mere risk factors such as high cholesterol or high blood pressure, but the actual lesions bearing direct responsibility for cardiovascular disease: atherosclerotic plaques.

“It seems that heart disease may be driven by our immune system’s inability to ‘take out the trash,’” said Nicholas Leeper, MD, associate professor of vascular surgery and of cardiovascular medicine.

A study describing the researchers’ findings will be published in Nature. Leeper is the senior author.

Atherosclerosis is caused by the deposition of fatty substances along arterial walls. Over the years, these substances form plaques. It’s now known that numerous dead and dying cells accumulate in atherosclerotic plaques, which inflammation renders brittle and vulnerable to rupture, the ultimate cause of heart attack and stroke.

Immune cell malfeasance

Contributing to the pathology is malfeasance on the part of a class of immune cells that first arrive at the site with presumably benign intentions, said Leeper.

“Even a perfectly healthy body turns over more than 100 billion cells a day, every day,” he said. “One of the several jobs performed by immune cells called macrophages – from the Greek words for ‘big eater’ – is to come and gobble up those dead and dying cells, which might otherwise begin releasing substances that can foster inflammation.”

Many cells in the human body feature a “don’t eat me” signal on their surface: a protein called CD47. The protein tells the immune system that a cell is alive, still going strong and part of a person’s healthy tissue.

Normally, as a cell approaches death, its CD47 surface proteins start disappearing, exposing the cell to macrophages’ garbage-disposal service. But atherosclerotic plaques are filled with dead and dying cells that should have been cleared by macrophages, yet weren’t. In fact, many of the cells piling up in these lesions are dead macrophages and other vascular cells that should have been cleared long ago.

“The fact that there are so many dying cells in an atherosclerotic plaque, although those sick cells are supposed to be cleared promptly by macrophages, got us thinking,” said Yoko Kojima, MD, PhD, a basic life science research associate who is the study’s lead author.