A new study opens the door to new therapeutic targets in glioblastoma, the most common and most malignant tumor among glial neoplasms. The authors, researchers at the Institute of Neurosciences of Alicante, have identified a previously unknown mechanism that allows the tumor to reprogram brain cells to inactivate their function of triggering an immune system response.
Researchers at the Institute of Neurosciences of Alicante, a joint center of the Superior Council of Scientific Research (CSIC) and the Miguel Hernández de Elche University, identified this mechanism that allows glioblastoma escape from the immune system and keep progressing. The research was conducted in collaboration with the Clinical Hematology Service of the Hospital Virgen de la Arrixaca-IMIB of the University of Murcia and the Albert Einstein College of Medicine.
The finding, published in the journal Oncotarget, opens the door to new therapies not directly directed against the tumor, but against a type of cells called pericytes, which surround the blood vessels in the brain and play a crucial role in the inappropriate immune system response.
“Glioblastoma cells act on other [cells] that surround blood vessels in the brain called pericytes, responsible for triggering in normal conditions the immune response. The interaction with malignant glioblastoma cells prevents pericytes start the immune response. Consequently, the destructive T cells become unable to attack the tumor. The brain does not detect the glioblastoma and cannot react to it,” said Salvador Martinez, director of the Experimental Neurobiology Group at the Neurosciences Institute, who led the research.
This work shows for the first time that the interaction with the tumor cells is what makes pericytes to promote tumor development instead of suppress it. Martinez group has also found that when blocking the action exerted by glioblastoma cells in pericytes, the tumor cannot cancel the immune response making it susceptible to be destroyed. This interference of glioblastoma in the immunosuppressive function of pericytes may represent a novel target for the development of new therapies.
In fact, there are several candidate molecules that can act on that interaction. “If we can prevent tumor cells interacting with pericytes, the immune system will react to the tumor and destroy it,” says Martinez.
“We have seen that this immunosuppressive mechanism depends on the interaction between PD-1 and PD-L1 receptors. Currently clinical trials are carried out with molecules against these receptors. One drawback is that these molecules are being administered intravenously, so they have to cross the blood brain barrier that isolates the brain, making them less effective,” says Martinez.
“If, instead of intravenous, this experimental therapy is administered by a lumbar puncture, to be distributed through the cerebrospinal fluid, it would be more likely to be more effective. It is what we will now test in animal models. If we can repetitively demonstrate in these animal models that the method is not toxic and safe, and administration by lumbar puncture is, we could go to a clinical trial. We hope to carry out these experiments,” he says.
Another strong point of this study was the use of grafts of human glioblastoma cells in mice (xenografts) capable of immune response, making the experimental model used more relevant to show an immune-regulatory mechanism that activated human glioblastoma. With it, they have shown that immunocompetent mice are unable to reject the human glioblastoma, because of the potent ability of glioblastoma cells to induce immune tolerance.