2024-10-09 09:45:00
Our body has a mechanism to destroy everything that attacks it, be it viruses, bacteria or tumor cells: the immune system. Cancer proliferates when tumor cells trick this system, preventing it from working against them. Cancer immunotherapy uses drugs aimed at preventing this blockage of the immune system by tumor cells, but immunotherapy does not always work.
In the case of brain metastases, i.e. when the tumor that arises in an organ spreads to the brain, immunotherapies have been attempted, with conflicting results.
“Brain metastases represent a serious clinical problem,” explains Manuel Valiente, head of the Brain Metastasis group at Spain’s National Cancer Research Center (CNIO) and director of a new study on the topic. “Patients with advanced brain metastases, i.e. those who already perceive symptoms of metastases, do not respond well to immunotherapy. But, also, it is increasingly common for patients who have responded well to immunotherapy to relapse, and this is often due to new metastases in the brain.”
Immunotherapy with blocking antibodies does not appear to be the optimal system against brain metastases. One possible cause is the existence of the blood-brain barrier, a type of permeable membrane that filters blood entering the brain to defend it from toxic agents. But this vascular barrier also makes it difficult for antibodies used in immunotherapy to enter. Without antibodies, immunotherapy doesn’t work.
Astrocytes siding with cancer
The CNIO group now proposes a very innovative hypothesis to combat this problem.
“We discovered – explains Neibla Priego of the CNIO, 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 the case of brain metastases they abuse this function because they are influenced by tumor”.
Perverted by cancer, astrocytes take the side of tumor cells when there are brain metastases. The interaction of astrocytes with the immune system, something that should be a normal process of immunomodulation, becomes a mechanism that fuels cancer, because astrocytes make it difficult for defensive cells to work 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 (lymphocytes, in green). Some of them have started to activate the factor inducing the molecule TIMP1 (in red), which will allow them to deactivate the action of lymphocytes 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. “Protumor astrocytes produce TIMP1, and this protein is involved in deactivating defensive cells that are supposed to kill tumor cells,” says Priego.
Once it has been demonstrated that this molecule, TIMP1, acts on the cells of the immune system, making them more ineffective, the CNIO team proposes using it as a biomarker to identify brain metastases affected by this mechanism of immunosuppression.
“TIMP1 is a good biomarker, because in patients with brain metastases it is secreted in significantly higher quantities into the cerebrospinal fluid,” says Priego.
Drug under investigation against protumoral astrocytes
The study goes further. Manuel Valiente’s group proposes a therapeutic alternative aimed at astrocytes: the combined use of immunotherapy with inhibitors that prevent the production of the TIMP1 molecule.
“There is a drug called silibinin, already used for compassionate use, which inhibits the production of the TIMP molecule,” says Valiente. “There is already an ongoing clinical study to test its therapeutic efficacy in brain metastases. 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 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 immunomodulators, neither in general studies nor, obviously, 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”, underlines Valiente.
The study is titled “TIMP1 mediates astrocyte-dependent local immunosuppression in brain metastases by acting on infiltrating CD8+ T cells.” And it was published in the academic journal Cancer Discovery. (Source: CNIO)
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