Targeting an Immune Regulating Protein May Help Halt Glioblastoma Progression

A new study details a discovery by investigators in Texas and China, which sheds light on what makes glioblastoma so hard to stop and offers new insight into how to halt its progression.

Glioblastomas are malignant Grade IV tumors made up of abnormal astrocytic cells. With this aggressive and lethal brain cancer, tumors readily spread into nearby brain tissue, and at times, to the opposite side of the brain.

While there is no cure for glioblastoma, investigators at the University of Texas MD Anderson Cancer Center are working on the Glioblastoma Moon Shot program, which is part of an ambitious plan to accelerate the termination of 13 types of cancer.

More specifically, a team of investigators from the University of Texas MD Anderson Cancer Center and the Beijing Institute for Brain Disorders examined the functional role of fibrinogen-like protein 2 (FGL2)—a membrane-bound or secreted protein expressed by macrophages, T cells, and tumor cells that have coagulation activity or immune-suppressive functions—in glioblastoma.

According to the new study, prior research has found that FGL2 promotes mammary tumor progression and is a key hub of tumor-mediated immune suppression in glioblastoma multiforme. However, its functional role at the molecular and cellular levels has been mostly unknown.

In the current study, investigators found that high expression of FGL2 in glioblastoma allows the protein to control a specialized group of CD103 dendritic cells, which are necessary for the activation of tumor-killing T cells. In addition, investigators discovered that these dendritic cells can only activate T cells by making their way to the tumor microenvironment in the central nervous center.

By using a FGL2 neutralization, or “knockout” therapy on tumor cells, investigators found they could achieve FGL2 “knockout” and eliminate tumor progression in mice with intact immune systems. In an interview with Rare Disease Report®, study co-lead Shulin Li, PhD, explained that the research team is testing other types of Fgl2 neutralization therapy, with promising results. “We have a Fgl2 neutralization cell therapy ready for clinical trials whenever clinicians are ready,” said Li.

Along with these findings, the investigators analyzed human glioblastoma from The Cancer Genome Atlas and found that lower levels of FGL2 protein expression coupled with other factors was associated with longer survival of glioblastoma patients.

“GBM is a deadly disease because of its aggressive growth, invasion of surrounding tissues, and poor immunogenicity. Here we show that knockout of FGL2 in tumor cells induces adaptive immune responses, resulting in 100% tumor suppression in GL261, DBT, and LLC brain tumor model systems,” the study’s authors wrote. “These unexpected results suggest that FGL2 in tumor cells could serve as a potential therapeutic target for treating brain tumors and preventing tumor relapse. Supporting this conclusion, our previously published data showed that blocking FGL2 prolonged survival.”

About 15% of all primary brain tumors are glioblastomas. The median survival time for adults with glioblastoma can range from 11 to 31 months depending on the type of tumor, and tumor growth can be slowed by radiation and chemotherapy following surgery

The study, titled, “FGL2 promotes tumor progression in the CNS by suppressing CD103⁺ dendritic cell differentiation,” was published online in Nature Communications.