Attacking Cancer by Disabling Macrophage Recognition of CD47 "Don't Eat Me" Marker

CD47 is a "don't eat me" decoration found on the surface of cells. This is a necessary mechanism for the prevention of autoimmunity, but it is also subverted by cancer in order to prevent the innate immune system from attacking tumor cells. The cancer research community has investigated a range of approaches to prevent CD47 from holding back the immune response to cancerous cells. One possibility, demonstrated here, is to engineer the innate immune cells known as macrophages in order to block the CD47 interaction and thus ensure an aggressive response to cancerous cells.

Cancer remains one of the leading causes of death in the U.S. at over 600,000 deaths per year. Cancers that form solid tumors such as in the breast, brain, or skin are particularly hard to treat. Surgery is typically the first line of defense for patients fighting solid tumors. But surgery may not remove all cancerous cells, and leftover cells can mutate and spread throughout the body. "Due to a solid tumor's physical properties, it is challenging to design molecules that can enter these masses. Instead of creating a new molecule to do the job, we propose using cells that 'eat' invaders - macrophages."

Macrophages, a type of white blood cell, immediately engulf and destroy - phagocytize - invaders such as bacteria, viruses, and even implants to remove them from the body. A macrophage's innate immune response teaches our bodies to remember and attack invading cells in the future. This learned immunity is essential to creating a kind of cancer vaccine. "Macrophages recognize cancer cells as part of the body, not invaders. To allow these white blood cells to see and attack cancer cells, we had to investigate the molecular pathway that controls cell-to-cell communication. Turning off this pathway - a checkpoint interaction between a protein called SIRPa on the macrophage and the CD47 protein found on all 'self' cells - was the key to creating this therapy."

The engineered macrophages were put to the test on "tumoroids," conglomerates of mouse melanoma cells in culture plates. The macrophages cooperatively clustered around the cancer cells, picked them apart and progressively destroyed the tumor. When tested in vivo, the engineered cells were able to eliminate tumors in 80% of mice. Importantly, tumor elimination triggered an adaptive immune response. Weeks later, the anti-cancer immunoglobulin G antibody increased. This engineered macrophage therapy works best in combination with existing antibody therapy. One day, patients may be able to rely on these engineered cells to eliminate solid tumors as well as the need for future treatments.