The Story of CSF1R

Cancer puts the immune system’s “vacuum cleaners” to work.

Macrophages, when I first learned about them, seemed like the immune system’s friendly neighborhood vacuum cleaners, scarfing up dead bits of cells and other garbage in the body’s tissues.

I saw pictures of 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.

CSF1R and CSF1 are cell-surface proteins that are part of your immune response

CSF1R stands for colony stimulating factor 1 receptor – it’s a protein on the surface of a cell that can bind to another protein, colony stimulating factor 1 When these two proteins connect, they kick off a series of events that are important for many things that happen in the body, from helping bones and teeth develop to making changes in the mammary gland during pregnancy. These proteins play critical roles in the immune and inflammatory system.

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 began growing while you were 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 helps these hungry cells — their name comes from Greek words which together mean “big eater” – 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 that 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.

Cancers can use CSF1 and CSF1R to help tumors grow

Tumor cells can produce CSF1, calling more macrophages to the tumor site. Scientists looking at cancer have found that CSF1R is expressed in unusual numbers in some tumors. Macrophages associated with the tumor can act to help the tumor, rather than the immune system, by making compounds that help the tumor grow and spread. They’re working to “heal” the tumor, rather than the body. In many cancers, having more macrophages at the tumor site means that the person’s prognosis is worse.

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 that weaken the body’s defense against cancer; one way they do this is by blocking the signal to other cells in the immune system and help tumors grow and spread instead. They also work 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.

Researchers are using CSF1/CSF1R as a gateway to new treatments

Several potential medications that use the CSF1/CSF1R connection and the reactions that follow are in clinical trials for a range of cancers, including breast and prostate cancer. Researchers are looking at molecules, including antibodies, that prevent CSF1 and CSF1R from binding to each other. They’re also studying ways to throw a kink in the chain of events that follows this binding, using other compounds. These drugs include IMC-CS4 and RG7155, which are antibodies to the CSF1 receptor, and quizartinib, which inhibits CSF1R and similar proteins, called tyrosine kinases.

Scientists are now working to use aspects of the interaction between tumor-produced CSF1 and the macrophages’ CSF1 receptor 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 and more T cells appeared in the tumor area, while 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 to not 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 with them.

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