Miguel Bronchud: Astrocyte-dependent local immunosuppression in brain metastasis

Miguel Bronchud, Co-Founder of Regenerative Medicine Solutions, shared on LinkedIn:

“Spanish National Center for Cancer Research (CNIO , Madrid) researchers have discovered that some cancers pervert certain brain cells different from neurons , the astrocytes, and causes them to produce a protein that works in favour of the tumour.

A drug, silibinin, inhibits this protein, and could be used in clinical trials to verify if safe and effective to help treat brain metastasis with immunotherapy? A preliminary clinical trial is underway. But the truly important thing is that the approach is an original one and that brain metastasis are still very much an unmet clinical need.

Whether the proposed combination is going to be safe or effective will depend on clinical trial results.

The work is published in the American Association for Cancer Research’s journal Cancer Discovery.

TIMP1 mediates astrocyte-dependent local immunosuppression in brain metastasis acting on infiltrating CD8+ T cells.
Neibla Priego et al (2024)

“Immunotherapies against brain metastases have shown clinical benefits when applied to asymptomatic patients, but they are largely ineffective in symptomatic cases for unknown reasons. Authors dissect the heterogeneity in brain metastasis-associated astrocytes using scRNAseq and report a population that blocks the antitumoral activity of infiltrating T cells. This pro-tumoral activity is mediated by the secretion of TIMP1 from a cluster of pSTAT3+ astrocytes that acts on CD63+ CD8+ T cells to modulate their function.”

Using genetic and pharmacologic approaches in mouse and human brain metastasis models, these Spanish researchers demonstrate that combining immune checkpoint blockade antibodies with the inhibition of astrocyte-mediated local immunosuppression may perhaps benefit patients with symptomatic brain metastases.

In any case, presence of TIMP1 in liquid biopsies (particularly of cerebrospinal fluid or CSF obtained by lumbar puncture) provides an interesting promise of useful biomarker to select patients for this combined immunotherapy? To be confirmed by prospective studies and other labs, but clearly good news.

In summary- 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.

Having demonstrated that this molecule, TIMP1, acts on immune system cells and renders them less effective, the CNIO team proposes to use it as a biomarker to detect brain metastases affected by this immunosuppressive mechanism. ‘IMP1 is a good biomarker, because it is secreted in significantly higher amounts in the cerebrospinal fluid of patients with brain metastases,’ says Priego.

Drug targeting pro-tumour astrocytes in trials? Which of the different types of astrocytes? How? When?”

TIMP1 mediates astrocyte-dependent local immunosuppression in brain metastasis acting on infiltrating CD8+ T cells | Cancer Discovery

Authors: Neibla Priego, Ana de Pablos-Aragoneses, Maria Perea-García, Valentina Pieri, Carolina Hernandez-Oliver, Laura Alvaro-Espinosa, Andrea Rojas, Oliva Sanchez, Ariane Steindl, Eduardo Caleiras. Fernando Garcia, Santiago Garcia-Martin, Osvaldo Grana-Castro, Sandra Garcia-Mulero, Diego Serrano, Paloma Velasco-Beltran, Borja Jimenez-Lasheras, Leire Egia-Mendikute, Luise Rupp, Antonia Stammberger, Matthias Meinhardt, Anas Chaachou-Charradi, Elena Martínez-Saez, Luca Bertero, Paola Cassoni, Luca Mangherini Alessia Pellerino, Roberta Ruda, Riccardo Soffietti, Fatima Al-Shahrour, Paul Saftig, Rebeca Sanz-Pamplona, Marc Schmitz, Stephen J. Crocker, Alfonso Calvo, Asis Palazon, RENACER Group, Manuel Valiente.