Possible new treatment against brain metastasis

Our body has a mechanism to destroy everything that attacks it, whether viruses, bacteria or cancer cells: the immune system. Cancer proliferates when tumor cells trick this system, preventing it from activating against them. Cancer immunotherapy uses drugs aimed at preventing this blockage of the immune system by cancer cells, but immunotherapy does not always work.

In the case of brain metastasis, that is, when the tumor that has arisen in an organ spreads to the brain, immunotherapies have been tried, with mixed results.

“Brain metastasis poses a serious clinical problem,” explains Manuel Valiente, head of the Brain Metastasis group at the National Cancer Research Center (CNIO) of Spain and director of a new study on the matter. “Patients with advanced brain metastasis, that is, those who already perceive the symptoms of metastasis, do not respond well to immunotherapy. But, in addition, it happens more and more frequently that patients who did respond well to immunotherapy relapse, and it is often due to new metastases in the brain.”

That is, immunotherapy with blocking antibodies does not seem to be the optimal system against brain metastasis. A possible cause is the existence of the blood-brain barrier, a type of permeable membrane that filters the blood that enters the brain to defend it from toxic agents. But this vascular barrier also makes it difficult for the antibodies used in immunotherapy to enter. Without antibodies, immunotherapy does not work.

Astrocytes that take sides with cancer

The CNIO group now proposes a very innovative hypothesis to combat this problem.

“We have discovered – explains Neibla Priego of the CNIO, the first signatory of the study – that a type of 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 of this function because they are influenced by the tumor.”

Perverted by cancer, astrocytes take the side of tumor cells when there is brain metastasis. The interaction of astrocytes with the immune system, something that should be a normal immunomodulation process, becomes a mechanism that fuels cancer, because astrocytes make the work of defensive cells difficult and prevent them from killing tumor cells.

Cells around a brain metastasis in an animal model: several brain cells (astrocytes, in white) surround an immune system cell (lymphocyte, in green). Some of them have begun to activate the TIMP1 molecule-inducing factor (in red), which will allow them to disable the action of the lymphocyte against tumor cells. (Image: CNIO)

A biomarker of metastasis against which immunotherapy will not work

The CNIO group has identified a key molecule in the process, called TIMP1. “Protumoral astrocytes produce TIMP1, and this protein is involved in disabling the defensive cells that should kill cancer cells,” says Priego.

Once it has been shown that this molecule, TIMP1, acts on the cells of the immune system and makes them more ineffective, the CNIO team proposes using it as a biomarker to detect brain metastases affected by this immunosuppression mechanism.

“TIMP1 is a good biomarker, because in patients with brain metastasis it is secreted in significantly higher quantities in the cerebrospinal fluid,” says Priego.

Drug in trial against pro-tumor astrocytes

The study goes further. Manuel Valiente’s group proposes a therapeutic alternative that targets astrocytes: the combined use of immunotherapy with inhibitors that prevent the production of the TIMP1 molecule.

“There is a drug called silibinin, which has already been used in compassionate use, which inhibits the production of the TIMP molecule,” says Valiente. “There is already a clinical trial underway to test its therapeutic efficacy in brain metastasis. We hope to have the results in 2025.”

The goal is to combine TIMP1 inhibition with traditional immunotherapy, “which would increase the potency of the therapeutic strategy and facilitate its incorporation into clinical protocols,” explains Valiente.

Advancement in basic knowledge

This researcher also highlights the other value of the work: revealing the role of astrocytes in the disease, unmasking their heterogeneity and thus allowing us to attack only those subtypes of astrocytes with an altered and negative function for the patient. “Until now, astrocytes had not been considered as immunomodulators, neither in general studies nor, of course, in relation to brain tumors. Our research is not only innovative from a clinical point of view, it is also very innovative for the advancement of scientific knowledge,” Valiente emphasizes.

The study is titled “TIMP1 mediates astrocyte-dependent local immunosuppression in brain metastasis acting on infiltrating CD8+ T cells.” And it has been published in the academic journal Cancer Discovery. (Source: CNIO)