Antibodies to the proteins PD–1 and PD–L1 have been shown to fight cancer by unleashing the body’s T cells, a type of immune cell. Now, researchers led by Irv Weissman, director of the Ludwig Center at Stanford, have shown that the therapy also fights cancer in a completely different way: by prompting immune cells called macrophages to gobble up cancer cells. The finding may have important implications for cancer immunotherapy.

A paper describing the work, which was done in mice, was published online May 17 in the journal Nature.

T cells, which destroy damaged or diseased cells, can at times mistakenly attack healthy cells, causing autoimmune disorders like lupus or multiple sclerosis. PD–1 is an “immune checkpoint,” a protein receptor that tamps down highly active T cells to protect healthy tissue. Cancer cells exploit this safeguard for their own purposes, cranking up the expression of PD–L1 proteins that activate the PD–1 receptor. Cancer patients are now being treated with antibodies that block the PD–1 receptor.

“While most investigators accept the idea that anti–PD–1 and PD–L1 antibodies work by taking the brakes off of the T–cell attack on cancer cells, we have shown that there is a second mechanism that is also involved,” said Weissman, who is also director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine.

Weissman and his colleagues show in their paper that PD–1 activation also inhibits the anti–cancer activity of immune cells called macrophages, which are induced to create the PD–1 receptor on their surface when they infiltrate tumors. Blocking the PD–1 receptor with antibodies prompted macrophages to attack cancer cells. It’s unclear to what degree macrophages are responsible for the therapeutic success of anti–PD–1 and anti–PD–L1 antibody therapies, but the practical implications of the discovery could be important. The finding could lead to improved therapies for cancer that activate both T cells and macrophages. It also suggests that those therapies may be more potent and broadly effective against cancers than previously believed.