When CSF1R works properly, it controls how the immune system’s first responders—macrophages—operate. A CSF1R mutation can cause macrophages to repair cancer cells instead of the the body’s cells, and can dampen the immune system’s response to cancer by keeping other beneficial processes away from the tumor.
In many cases, having more macrophages at a tumor site means the patient’s prognosis is worse.
A significant percentage of breast cancer, ovarian cancer, prostate cancer, endometrial cancer, and other cancers show high levels of CSF1R proteins.
CSF1R mutation testing requires a tumor sample, ideally from a recent biopsy.
Several treatments that target the CSF1R protein’s connection with the protein CSF1 are in clinical trials for a range of cancers, including breast and prostate cancer.
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Macrophages seem like the immune system’s friendly neighborhood vacuum cleaners, scarfing up dead bits of cells and other garbage in the body’s tissues.
In pictures you can see them swallowing up whole cells, stretching out cell-like “arms” to capture parasites. But when it comes to cancer, macrophages can sometimes turn from helpful cells that sweep away your body’s jetsam to big bad blobs that work for the tumor itself.
No matter which side they’re on, many macrophages start out as a type of white blood cell called a monocyte. Monocytes are made in the bone marrow and cruise around the body in the bloodstream. When they come across a damaged tissue or other problem spot, they leave the bloodstream to help, and can start turning into macrophages. Some tissues already have their own resident macrophages that begin growing while the body’s still an embryo. Researchers recently found that the spleen can produce its own monocytes and macrophages, too, and may play a role in cancer as a result.
However they get their start, when your body has an infection, macrophages are often the first responders at the scene. They can send out chemical signals to call more immune cells to help. Some macrophages can even start the healing process by releasing other compounds that encourage new cells to grow.
One of the things that help these hungry cells—their name means “big eater” in Greek—do their work is a protein called CSF1R, made by a gene with the same name. (The receptor has also been called macrophage colony stimulating factor, or MCSFR.) This protein—its full title is colony stimulating factor 1 receptor—can appear on the cell surface of macrophages. When your body is injured, damaged cells may send out a protein signal called CSF1.
When CSF1 and the CSF1 receptor hook up, their connection kicks off a series of reactions that bring more macrophages to the injury site. These macrophages can do everything from sending out a chemical call for help to other immune cells to helping wounds heal by encouraging the creation of new blood vessels.
But a tumor can make use of the macrophages and these proteins to help itself grow. For a tumor is more than just a lump of cancer—a tumor is its own little ecosystem, which may include blood vessels, tissue, and a host of cells that work to keep the tumor thriving.
Macrophages have been found in this tumor environment in many types of cancer. Some might travel from elsewhere in the body, beckoned by the tumor. Others may be produced by the tumor itself.
Wherever they come from, having many macrophages gathering around the tumor can actually suppress the immune system and prevent it from working against the tumor. In most cancers studied in humans, the more macrophages you have around the tumor, the worse off you’re likely to be. These gobbling cells have been found clustered around the leading edge of the tumor, where they may be helping the tumor cells grow and spread.
Tumor cells can produce the CSF1 protein that draws macrophages to the site; in fact, some studies have shown that tumors produce unusually large amounts of this protein. The connection between this protein and the CSF1R protein on the macrophages’ surface kicks off the series of reactions that will make more macrophages, and make them stronger—but this time, in service of the tumor itself.
Instead of helping your immune system, macrophages that are associated with tumors weaken the body’s defense against cancer. One way they do this is by blocking the signal to other cells in the immune system. They also use the same healing properties they use during a normal injury to “heal” the tumor. A macrophage can even help tumor cells slip into blood vessels—through a series of steps that also involves CSF1—which can help cancer spread from a single spot to other locations in the body.
For certain cancers, people have started looking more closely at how CSF1R may be affecting the tumor in hopes of using what they learn to shut the tumor down. In breast cancer, researchers have found that the cancer cells can make CSF1R that works not only at the cell surface, but in the cells’ nuclei as well.
Scientists are now working to use aspects of the interaction between tumor-produced CSF1 and the macrophages’ CSF1 receptors to either turn these macrophages back to the body’s helpful immune system force or to get rid of the turncoats. Some people are trying to prevent the receptor and compound from meeting up; others are looking at stopping some of the things that happen once they do meet. In tests, tumor-carrying mice treated with antibodies that block the receptor or other small molecules that shut off the pathway have had tumors shrink and lived longer overall; these treatments encouraged macrophages to work against the tumor rather than for it. Treatments like these have also seemed to make chemotherapy and other cancer treatments—like adoptive cell transfer, in which immune cells are grown in the lab and then re-infused into the body—work better in mice.
There are also many clinical trials underway that are looking at how interfering with the macrophages’ CSF1 receptors can help people. In a study last year, a group of researchers created antibodies to the CSF1 receptor and gave the treatment to several people who had a disease called diffuse-type giant cell tumor, which involves large joints. After being given the antibodies, people began to have reduced symptoms, more T cells appeared in the tumor area, and fewer macrophages with CSF1R were spotted. One 19-year-old woman had a tumor in her ankle that started to disintegrate after several weeks of antibody treatment.
Researchers say they need to be careful not to wipe out macrophages’ friendly functions, or to tamper with them in the few cancers, like colorectal cancer, in which more macrophages actually mean people are faring better. But trying to shut down these macrophages-gone-wrong—as well as the CSF1 protein and receptor that kick off their bad habits—may be yet another way to weaken a tumor, and strengthen the immune system of the person who’s carrying it.