Macrophages / Darryl Leja, NHGRI

A secondary mechanism of action of existing anti-cancer therapy has been identified by researchers at Stanford University School of Medicine. The research, published in Nature, demonstrated that blocking PD-1 and PD-L1 interactions caused macrophages to target and engulf cancer cells, alongside the primary mechanism of activating T-cells.

PD-1 is a cell receptor that helps to protect healthy tissues from an overactive immune system. T-cells will occasionally activate an immune response against healthy cells by accident, resulting in the cells being destroyed. To prevent this, the body has developed PD-1 to release a ‘do not kill’ signal in tissues that are free of infection or damage.

Previous research has shown that cancer cells can hijack this system by producing PD-L1 proteins to activate the receptors and mimic the signal. In doing so, the cancer can repress the host’s immune system and prevent the disease from being targeted, ensuring proliferation. Researchers have taken advantage of this system to develop an anti-cancer therapy that involves providing the patients with PD-1 antibodies, blocking the receptor’s interaction with PD-L1 and killing the signal.

“Using antibodies to PD-1 or PD-L1 is one of the major advances in cancer immunotherapy,” said Irving Weissman, M.D., senior author and Director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine. “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.”

Using mice, the team found that activation of PD-1 also inhibited the ability of macrophages, another component of the immune system, from engulfing and destroying cancer cells. By preventing receptor activation with antibodies, the macrophages were reactivated.

“Macrophages that infiltrate tumours are induced to create the PD-1 receptor on their surface, and when PD-1 or PD-L1 is blocked with antibodies, it prompts those macrophage cells to attack the cancer,” said Sydney Gordon, lead author.

The mechanism the team observed was very similar to that of another antibody studied in the Weissman lab. The team have previously demonstrated that antibodies for the CD47 protein are capable of directing macrophages towards cancer cells and this research is currently being testing in small-scale clinical trials in humans.

While it seems likely that the secondary effect of PD-1 antibodies contributes to their success in cancer treatments, it is currently unclear what the magnitude of this effect is. It does, however, provide an insight into how the treatment might be further developed in the future and may indicate that the therapy is suitable for a broader selection of patients than initially suspected.

“In order for T-cells to attack cancer when you take the brakes off with antibodies, you need to start with a population of T-cells that have learned to recognize specific cancer cells in the first place,” Weissman said. “Macrophage cells are part of the innate immune system, which means they should be able to recognize every kind of cancer in every patient.”