Why do some brain tumors response to immunotherapy?

Glioblastoma is a malignant and invasive brain tumor. Patients usually have surgical removal of the tumor as much as possible, followed by radiation and chemotherapy. However, the prognosis of glioblastoma is very severe, with a high recurrence rate and low survival rate. And the patient's general survival is about 15 months.

Under normal conditions, the body's own immune system can detect and destroy cancer cells. However, tumor cells promote the growth of cancer cells by over-expressing immune checkpoint proteins , thereby inhibiting the immune system response, and escaping human immune surveillance and killing. PD-1 is such an immune checkpoint protein. Immune checkpoint inhibitors , such as PD-1 inhibitors, achieve anti-tumor effects by suppressing the activity of checkpoint poimts , releasing immune "brakes" in the tumor microenvironment, and re-activating the immune response of T cells to tumors.

Considered the success of PD-1 inhibitors in other cancers, doctors hope that immunotherapeutics can help patients with glioblastoma.

A study led by researchers at Columbia University has revealed why some glioblastomas respond to immunotherapy. The study was published online in the journal Nature Medicine.

Fewer than one in 10 patients with glioblastoma responded to immunotherapy, a remarkable success in the past few years in treating a variety of aggressive cancers. But we can not know in advance which glioblastoma patients will respond to immunotherapy.

To understand why only a few of these tumors responded to immunotherapeutic drugs, the research team comprehensively analyzed the tumor microenvironment of 66 patients with glioblastoma before and after treatment with a PD-1 inhibitor (nivolumab or pembrolizumab), including the tumor itself and all the cells that support it. 17 of them responded to the drug for 6 months or longer.

They found that non-responsive tumors have more mutations in a gene called PTEN, which leads to higher levels of macrophages. Macrophages are a class of immune cells that usually help the body fight bacteria and other invaders. However, in glioblastoma, macrophages release many growth factors that promote survival and proliferation.

At the same time, cancer cells in tumors with PTEN mutations also tightly clump together, preventing immune cells from penetrating the tumor and its microenvironment.

Previous studies have shown that the PTEN gene is abnormally present in glioblastoma and other tumors. PTEN gene is considered to be a tumor suppressor gene with a wide range of changes and closely related to tumorigenesis following the p53 gene. And a study also has demonstrated that PTEN protein can inhibit tumor development by antagonizing the activity of tyrosine kinase FAK.

On the other hand, responsive tumors have more mutations in the MAPK signaling pathway , which helps to regulate essential cellular functions.

These mutations occur before patients receive PD-1 inhibitor therapy, so detecting mutations may provide a reliable way to predict which patients are likely to respond to immunotherapy.

The study also indicated that glioblastoma patients with MAPK mutations could benefit more from the combination of PD-1 inhibitors and MAPK-targeted therapy, although this combination requires clinical testing. MAPK targeted therapy has been approved for metastatic melanoma and is currently being tested for other cancers.

The findings help identify patients with glioblastoma who are most likely to benefit from immunotherapeutic drug therapy and develop new and more effective treatments.