Many patients with cancer are now treated with "checkpoint inhibitors." These new drugs release molecular brakes that ordinarily keep immune cells from running amok and damaging healthy tissues. But when these brakes lock up, they prevent the immune system from killing tissues that need killing -- tumors, for example. Always notoriously wily, cancer cells can learn how to paralyze the immune system by fooling its component cells into jamming on their brakes -- scientifically referred to as immune checkpoints -- causing their tumor-fighting behavior to screech to a halt.
One important immune checkpoint involves a signaling molecule called PD-1, which sits on the surface of many immune cells. Cancer cells all too often figure how to trigger excessive PD-1 signaling, which results in the demobilization of the immune system's rowdy warrior cells. That's just what you want to happen after, say, an infectious pathogen has been defeated or a tumor has been completely eradicated -- but not before. By blocking PD-1 signaling, checkpoint inhibitors delay premature immune-system demobilization until a cancer patient's tumor appears to be vanquished.
While immune-checkpoint hyperactivity renders a cancer patient's immune response too sluggish to detect, attack and defeat the patient's tumor, the situation is reversed in patients with one type of autoimmune disease -- and maybe other types, too. In a new twist described in a study in Proceedings of the National Academy of Sciences, Stanford immunologists Connie Weyand, MD, and Jorg Goronzy, MD, and their colleagues have discovered that in giant cell arteritis, in which the immune system attacks the aorta and its larger branches, the immune response is too strong because an immune checkpoint -- specifically, PD-1 signaling -- isn't braking hard enough.
This is the first time that a deficiency of an immune checkpoint has been implicated in a human autoimmune disease. But it might not be the last. "We expect that other autoimmune diseases may have similar checkpoint deficiencies," Weyand told me recently, "although the precise molecular mechanisms involved may vary from one autoimmune disease to the next."
Up to now, checkpoint-inhibitor drug development has been focused on impeding the PD-1 checkpoint in patients with cancer in order to amplify their anti-tumor immunity. The new study, Weyand hopes, will prompt the development of PD-1-invigorating drugs.