Engineering Macrophages to Ignore “Don’t Eat Me” Signals from Cancer Cells

Macrophages are one of the types of immune cell responsible for destroying potentially dangerous cells, such as those that have become cancerous. Unfortunately cancerous cells tend to circumvent the immune system by displaying molecules on their outer surface that cause macrophages to leave them alone. This is an abuse of recognition mechanisms that exist to protect other cell types. Researchers here show that producing engineered macrophages that ignore this signal can be a viable approach to cancer therapy, even though past attempts have proven too harmful to normal cells to proceed towards the clinic. Their new methodology manages to avoid the destruction of non-cancerous cells to any significant degree, which is a promising step forward for the use of macrophages in cancer immunotherapy.

One reason cancer is so difficult to treat is that it avoids detection by the body. Agents of the immune system are constantly checking the surfaces of cells for chemical signals that say they belong, but cancer cells express the same chemical signals as healthy ones. Without a way for the immune system to tell the difference, little stands in the way of cancer taking over. Now, researchers have learned how to re-engineer macrophages, the “first responders” of the immune system, so that they can distinguish between healthy and cancerous cells. Armed with this ability, the engineered cells were able to circulate through the body of a mouse, invade solid tumors and specifically engulf human cancer cells therein.

​​​​​​​”Our new approach takes young and aggressive macrophages from the bone marrow of a human donor and removes a key safeguard that cancer cells have co-opted to prevent them from being engulfed. Combined with cancer-specific targeting antibodies, these engineered macrophages swarm into solid tumors and rapidly drive regression of human tumors without any measurable toxicity.” Immune cell therapies using engineered T-cells have recently emerged as successful treatments for some blood cancers, which are referred to as “liquid” tumors. Tumors in other tissues are generally more solid, which can physically impede the ability of T-cells to penetrate into the mass of the tumor. Macrophages readily infiltrate diseased and damaged tissues, including tumors. As such, macrophage-based cancer therapies were investigated decades ago. While they were found to be safe in patients, they were not effective in destroying cancerous cells. It is now understood that such macrophages received the same “don’t eat me” signal from both healthy and cancerous cells.

It was since shown that a protein on human cells called CD47 functions as a “marker of self” by interacting with a protein on the surface of macrophages called SIRPA. When SIRPA contacts CD47 on any other cell, it serves as a safeguard that prevents the macrophage from engulfing the other cell, even if it’s cancerous. With that in mind, the researchers thought that controlling this protein might revitalize macrophage-based cell therapies. Injections of antibody molecules that block CD47 from interacting with SIRPA are already being tried in the clinic based on observations of some reduction in the sizes of tumors in mouse models. However, such molecular treatments reproducibly cause rapid loss of many circulating blood cells, as macrophages now attack some healthy cells as well. In addition to causing anemia, some mice with depleted CD47 die from autoimmune disease.

To get around these safety concerns and to potentially maximize therapeutic effects on tumors, researchers took fresh, young macrophages from human donors as well as mouse donors and directly blocked their SIRPA. They also injected various antibodies that bind to cancer cells, which help to activate macrophages that might enter the tumor. “The big surprise is that injected macrophages circulate all around the body but accumulate only within the tumors where they engorge on cancer cells.” After two injections, cancer cells were depleted 100-fold from tumors the size of a dime, and tumors regressed 80 percent in size. Importantly, blood cells were unaffected by the treatments, which suggests that this approach is safe.




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