TIMP1 Mediates Astrocyte-Dependent Local Immunosuppression in Brain Metastasis Acting on Infiltrating CD8+ T Cells.

in Cancer discovery by Neibla Priego, Ana de Pablos-Aragoneses, María Perea-García, Valentina Pieri, Carolina Hernández-Oliver, Laura Álvaro-Espinosa, Andrea Rojas, Oliva Sánchez, Ariane Steindl, Eduardo Caleiras, Fernando García, Santiago García-Martín, Osvaldo Graña-Castro, Sandra García-Mulero, Diego Serrano, Paloma Velasco-Beltrán, Borja Jiménez-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 Rudà, Riccardo Soffietti, Fatima Al-Shahrour, Paul Saftig, Rebeca Sanz-Pamplona, Marc Schmitz, Stephen J Crocker, Alfonso Calvo, Asís Palazón, , Manuel Valiente

TLDR

  • Researchers identified a population of astrocytes in brain metastases that produce TIMP1, which impairs the antitumoral activity of T cells, and found that combining immune checkpoint blockade with the inhibition of this immunosuppressive mechanism is effective in treating symptomatic brain metastases.
  • The study has significant implications for understanding immune modulation in brain tumors and offers new insights into potential therapeutic interventions.

Abstract

Immunotherapies against brain metastases have shown clinical benefits when applied to asymptomatic patients, but they are largely ineffective in symptomatic cases for unknown reasons. Here, we dissect the heterogeneity in metastasis-associated astrocytes using single-cell RNA sequencing and report a population that blocks the antitumoral activity of infiltrating T cells. This protumoral activity is mediated by the secretion of tissue inhibitor of metalloproteinase-1 (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, we demonstrate that combining immune checkpoint blockade antibodies with the inhibition of astrocyte-mediated local immunosuppression may benefit patients with symptomatic brain metastases. We further reveal that the presence of tissue inhibitor of metalloproteinase-1 in liquid biopsies provides a biomarker to select patients for this combined immunotherapy. Overall, our findings demonstrate an unexpected immunomodulatory role for astrocytes in brain metastases with clinical implications. Significance: This study presents a significant advancement in understanding immune modulation in brain tumors and offers new insights into the potential therapeutic interventions for brain metastases. See related commentary by Lorger and James, p. 11.

Overview

  • Researchers investigated the heterogeneity of astrocytes associated with brain metastases using single-cell RNA sequencing and identified a population that inhibits the antitumoral activity of T cells.
  • They found that a cluster of pSTAT3+ astrocytes produced TIMP1, which modulated the function of CD63+ CD8+ T cells by blocking their antitumoral activity.
  • The study aimed to understand the reasons behind the ineffectiveness of immunotherapies in treating symptomatic brain metastases and provide new insights into potential therapeutic interventions.

Comparative Analysis & Findings

  • Compared to asymptomatic patients, symptomatic patients with brain metastases showed a lack of response to immunotherapies, pointing to the presence of an unknown immunosuppressive mechanism.
  • Single-cell RNA sequencing revealed that a specific population of astrocytes produces TIMP1, which impairs the antitumoral activity of infiltrating T cells.
  • Combining immune checkpoint blockade antibodies with the inhibition of astrocyte-mediated local immunosuppression was found to be effective in treating symptomatic brain metastases in mouse and human models.

Implications and Future Directions

  • The study has significant implications for the understanding of immune modulation in brain tumors and offers new insights into the potential therapeutic interventions for brain metastases.
  • The presence of TIMP1 in liquid biopsies may provide a biomarker for selecting patients who would benefit from combined immunotherapy.
  • Future research may explore the potential of targeting astrocyte-mediated local immunosuppression in addition to immune checkpoint blockade in treating brain metastases.
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