Researchers at the Spanish National Cancer Research Center (CNIO) have discovered that in brain metastasis, cancer alters the course of certain astrocytes and causes them to produce a protein that works in the tumor’s favor. Their study also proposes a drug that inhibits the protein and could potentially be used to help treat brain metastasis with immunotherapy.
The work is published in Cancer Discovery in an article titled, “TIMP1 mediates astrocyte-dependent local immunosuppression in brain metastasis acting on infiltrating CD8+ T cells.”
“Brain metastasis poses a serious clinical problem,” explained Manuel Valiente, PhD, head of the CNIO Brain Metastasis Group and director of the study. “Patients with advanced brain metastases, that is, those who can already perceive symptoms of metastases, don’t respond well to immunotherapy. But even patients who respond well to immunotherapy increasingly relapse, often because of new metastases in the brain.”
We have discovered, explained Neibla Priego, PhD, first author of the paper, “that certain brain cells called astrocytes act as immunomodulators, that is, they interact with the immune system in the brain, and in cases of brain metastasis they misuse this function because they are being influenced by the tumor.”
Perverted in this way by cancer, astrocytes ally with tumor cells when brain metastasis occurs.
The team of researchers has identified a key molecule in the process, called TIMP1. “Pro-tumor astrocytes produce TIMP1, and this protein is involved in disabling the defensive cells that should kill cancer cells,” said Priego.
“TIMP1 is a good biomarker because it is secreted in significantly higher amounts in the cerebrospinal fluid of patients with brain metastases,” said Priego.
The researchers also proposed a therapeutic alternative that targets astrocytes: the combination of immunotherapy with inhibitors that prevent the production of the TIMP1 molecule.
“There is a drug called silibinin, which has already been employed on a compassionate use basis, which inhibits the production of the TIMP1 molecule,” explained Valiente. “A clinical trial is already underway to test its therapeutic efficacy in brain metastasis. We hope to have the results in 2025.”
“Until now, astrocytes have not been considered as immunomodulators, either in general studies or in relation to brain tumors. Our research is not only innovative from a clinical point of view, but also very useful for the advancement of scientific knowledge,” concluded Valiente.
