Cancer Discovery. CNIO researchers propose a new treatment for brain metastasis based on immunotherapy
They have discovered that cancer perverts a type of brain cell, astrocytes, and makes them produce a protein that works in favor of the tumor.
A drug, silibinin, inhibits this protein, and could be used to help treat brain metastases with immunotherapy. A clinical trial is underway.
The work is published in the journal Cancer Discovery, of the American Association for Cancer Research.
Researchers from the Spanish National Cancer Research Centre (CNIO) propose a new treatment for brain metastases that do not respond or respond poorly to immunotherapy, and provide a biomarker to predict in which cases it should be applied.
Our body has a mechanism to destroy everything that attacks it, whether it is viruses, bacteria or cancer cells: the immune system. Cancer proliferates when tumor cells trick this system, and prevent it from activating against them. Cancer immunotherapy uses drugs aimed at avoiding this blockage of the immune system by cancer cells , but immunotherapy does not always work.
In the case of brain metastasis – when a tumor that has arisen in an organ spreads to the brain – immunotherapy has recently been tested, with varying results.
“Brain metastasis poses a serious clinical problem,” explains Manuel Valiente , head of the Brain Metastasis group at CNIO and director of the study that has now published its results. “ Patients with advanced brain metastasis, that is, those who already perceive the symptoms of metastasis, do not respond well to immunotherapy. However, it is also increasingly common for patients who did respond well to immunotherapy to relapse, and often it is due to new metastases in the brain ,” adds Valiente, recipient of a grant from the European Research Council (ERC).
That is to say, immunotherapy with blocking antibodies does not seem to be the optimal system for brain metastasis . One possible cause is the existence of the blood-brain barrier, a kind of permeable membrane that filters the blood that enters the brain to protect it from toxins. But this vascular barrier also hinders the entry of the antibodies used in immunotherapy. Without antibodies, immunotherapy does not work.
Astrocytes that take the side of cancer
The CNIO group now proposes a highly innovative hypothesis to combat this problem. It is presented in the journal Cancer Discovery , published by the American Association for Cancer Research.
“We have discovered – explains Neibla Priego , first signatory of the article – that a type of brain cells called astrocytes act as immuno-modulators, that is, they interact with the immune system in the brain, and in cases of brain metastasis they misuse 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 process of immunomodulation, becomes a mechanism that feeds cancer, because astrocytes hinder the work of defensive cells and prevent them from killing tumor cells.
A biomarker of metastasis where immunotherapy will not work
The CNIO group has identified a key molecule in the process, called TIMP1 . “Pro-tumour astrocytes produce TIMP1, and this protein is involved in disabling the defensive cells that should kill cancer cells ,” says Priego.
Once it has been demonstrated that this molecule, TIMP1, acts on the cells of the immune system and makes them less effective, the CNIO team proposes using it as a biomarker to detect brain metastases affected by this immunosuppression mechanism.
“TIMP1 is a good biomarker because it is secreted in significantly higher quantities into the cerebrospinal fluid in patients with brain metastases,” 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, that inhibits the production of the TIMP molecule ,” says Valiente. “ There is already a clinical trial underway 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,” says 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 attacking 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 work has received funding from various national entities, such as the Spanish Association against Cancer, the Ministry of Economy, Trade and Enterprise (MINECO), the Carlos III Health Institute, the ‘la Caixa’ Foundation, the Ramón Areces Foundation or the Fundació La Marató de TV3. It has also received funding from international entities such as the European Research Council (ERC), the European Union through Next Generation funds, or the European Molecular Biology Organisation (EMBO).
About the Spanish National Cancer Research Centre (CNIO)
The Spanish National Cancer Research Centre (CNIO) is a public centre where nearly 500 scientists work to improve the prevention, diagnosis and treatment of cancer. Its scientific output places CNIO among the leading cancer research centres in the world. CNIO is also distinguished by its drug discovery programme, created to accelerate the development of personalised therapies. It is possible to contribute to CNIO’s research through its philanthropic initiative “Friends of CNIO”.
Reference article
Neibla Priego, Ana de Pablos, Manuel Valiente et al, TIMP1 mediates astrocyte-dependent local immunosuppression in brain metastasis acting on infiltrating CD8+ T cells, Cancer Discov (2024).
DOI: https://doi.org/10.1158/2159-8290.CD-24-0134
Source: CNIO
Date: 02.10.2024
Photo: Cells surrounding a brain metastasis in an animal model: several brain cells (astrocytes, white) surround an immune system cell (lymphocyte, green). Some of them have begun to activate the TIMP1-inducing factor (red), which will enable them to disable the lymphocyte’s action against the tumour cells. Credit: CNIO.
Note: The Nutrigenomics Institute is not responsible for the opinions expressed in this article.
