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.



By getting CAR T Cells to epxress the NAP (Neutrophil Activating Protein) from Helicobacter pylori when their CAR proteins are stimulated, it may be possible to make use of CAR T cells in immunosuppressive solid tumors:

"The use of immunotherapy to treat cancer is increasing and genetically modified immune cells called CAR-T cells are efficacious for treating blood cancer. Unfortunately, their efficiency is impaired in solid tumors due to local immune suppression in the tumor.

To avoid this problem, the Uppsala researchers have armed CAR-T cells by introducing a gene that encodes the immune stimulatory protein NAP (neutrophil-activating protein) from the bacteria Helicobacter pylori. When NAP is released from the CAR-T cells this creates a proinflammatory environment which directly combats the immunosuppressive microenvironment in solid tumors and strengthens the function of the CAR-T cells.

"We believe that this new technology to arm CAR-T cells has the potential to completely change CAR-T cell treatment. NAP, secreted from the armed CAR-T cells can revert the tumors from immunologically 'cold' to 'hot.' In addition, NAP can also recruit other types of immune cells that can attack the tumor cells that are not recognized by the CAR-T cells," says Di Yu, researcher at the Department of Immunology, Genetics and Pathology, who has led the study together with Professor Magnus Essand at the same department. "

Posted by: jimofoz at June 20th, 2023 9:55 AM
Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.