Altering the Tumor Microenvironment Yields Startling Results by Blocking Tumor-Associated Macrophages in Glioblastoma

Glioblastoma multiforme (GBM) is the most common and the most deadly adult primary brain tumor, with an average survival of just 14 months following diagnosis. Even with aggressive treatment by surgery, radiation, and chemotherapy, most therapeutic approaches targeting the glioma cells in GBM fail. Faced with this bleak picture, Johanna Joyce and colleagues at Memorial Sloan Kettering Cancer Center (MSKCC) in New York City looked for an alternative strategy and turned to non-tumor cells that are part of the glioma microenvironment, the cancer’s cellular neighbors. In particular, they zeroed in on tumor-associated macrophages and microglia (TAMs). The results were startling.

This image shows part of a glioblastoma tumor
from a mouse treated with a CSF-1R inhibitor.
The drug was shown to induce tumor-associated
macrophages (green) to phagocytose or
eat tumor cells (red).Glioblastoma multiforme (GBM) is the most common and the most deadly adult primary brain tumor, with an average survival of just 14 months following diagnosis. Even with aggressive treatment by surgery, radiation, and chemotherapy, most therapeutic approaches targeting the glioma cells in GBM fail. Faced with this bleak picture, Johanna Joyce and colleagues at Memorial Sloan Kettering Cancer Center (MSKCC) in New York City looked for an alternative strategy and turned to non-tumor cells that are part of the glioma microenvironment, the cancer’s cellular neighbors. In particular, they zeroed in on tumor-associated macrophages and microglia (TAMs). The results were startling.

TAMs are resident macrophages, which are normally the brain’s front-line immune cells, and depend on colony-stimulating factor-1 (CSF-1) for differentiation and survival. When the Joyce lab used an inhibitor of the CSF-1 receptor (CSF-1R) to target TAMs in a mouse model of GBM, the researchers saw dramatic changes. The treated mice survived many months beyond the control cohort. Their established, high-grade gliomas regressed in proliferation and malignancy, even though the glioma cells themselves were not the targets of the TAM treatment. With the TAMs blockaded by CSF-1 inhibitors, it was the tumor cells that showed increased rates of apoptosis (programmed cell death). The TAMs were not even depleted in the treated mice, despite the drug blockade of their growth factor. Instead the TAMs survived by responding to growth factors secreted by the gliomas, including GM-CSF and IFN-γ, according to Joyce.

Going one step further, the researchers found that tumor spheres, freshly isolated from glioma patients in the surgery department at MSKCC, responded to the drug when implanted in animals. The CSF-1R blockade slowed intracranial growth in the patient-derived glioma xenografts.

As the most common glioma, the GBM genome was the first to be sequenced for the Cancer Genome Atlas, which parsed GBM into four genetic subtypes: proneural, neural, classical, and mesenchymal. The mice used in the Joyce lab experiments model the proneural GBM subtype. All forms of GBM have a 2- to 3-person per 100,000 incidence rate in the United States and Europe, according to the National Brain Tumor Society. Because of its highly invasive phenotype, GBM is almost impossible to resect completely in surgery. Drug and radiation treatments are the standard followups.

Joyce says that these new results, which were first reported only two months ago in Nature Medicine, are encouraging for planned clinical trials in glioma patients, testing CSF-1R inhibitors in combination with radiation therapy. “We are optimistic that CSF-1R inhibitors may provide a more effective therapy than current treatments for the disease management of glioma patients,” Joyce says.