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

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Neibla Priego - , CIBER - Centro de Investigación Biomédica en Red (Autor:in)
  • Ana de Pablos-Aragoneses - , Centro Nacional de Investigaciones Oncológicas (CNIO), New York, NY, United States. (Autor:in)
  • Maria Perea-García - , CIBER - Centro de Investigación Biomédica en Red (Autor:in)
  • Valentina Pieri - , IRCCS Ospedale San Raffaele - Milano (Autor:in)
  • Carolina Hernandez-Oliver - , CIBER - Centro de Investigación Biomédica en Red (Autor:in)
  • Laura Alvaro-Espinosa - , CIBER - Centro de Investigación Biomédica en Red (Autor:in)
  • Andrea Rojas - , CIBER - Centro de Investigación Biomédica en Red (Autor:in)
  • Oliva Sanchez - , CIBER - Centro de Investigación Biomédica en Red (Autor:in)
  • Ariane Steindl - , Medizinische Universität Wien (Autor:in)
  • Eduardo Caleiras - , CIBER - Centro de Investigación Biomédica en Red (Autor:in)
  • Fernando Garcia - , CIBER - Centro de Investigación Biomédica en Red (Autor:in)
  • Santiago Garcia-Martin - , CIBER - Centro de Investigación Biomédica en Red (Autor:in)
  • Osvaldo Grana-Castro - , CIBER - Centro de Investigación Biomédica en Red (Autor:in)
  • Sandra Garcia-Mulero - , Universitat de Barcelona (Autor:in)
  • Diego Serrano - , Universidad de Navarra (Autor:in)
  • Paloma Velasco-Beltran - , CIC bioGUNE, Derio, Bizkaia, Spain. (Autor:in)
  • Borja Jimenez-Lasheras - , CIC bioGUNE, Derio, Bizkaia, Spain. (Autor:in)
  • Leire Egia-Mendikute - , CIC bioGUNE, Derio, Bizkaia, Spain. (Autor:in)
  • Luise Rupp - , Institut für Immunologie (Autor:in)
  • Antonia Stammberger - , Institut für Immunologie (Autor:in)
  • Matthias Meinhardt - , Institut für Pathologie (Autor:in)
  • Anas Chaachou-Charradi - , Hospital Universitari Vall d'Hebron (Autor:in)
  • Elena Martínez-Saez - , Hospital Universitari Vall d'Hebron (Autor:in)
  • Luca Bertero - , University of Turin (Autor:in)
  • Paola Cassoni - , University of Turin (Autor:in)
  • Luca Mangherini - , University of Turin (Autor:in)
  • Alessia Pellerino - , Azienda Ospedaliera - Universitaria Città della Salute e della Scienza di Torino (Autor:in)
  • Roberta Ruda - , Azienda Ospedaliera - Universitaria Città della Salute e della Scienza di Torino (Autor:in)
  • Riccardo Soffietti - , Istituto di Candiolo FPO-IRCCS (Autor:in)
  • Fatima Al-Shahrour - , CIBER - Centro de Investigación Biomédica en Red (Autor:in)
  • Paul Saftig - , Christian-Albrechts-Universität zu Kiel (CAU) (Autor:in)
  • Rebeca Sanz-Pamplona - , IISA, Zaragoza, Spain. (Autor:in)
  • Marc Schmitz - , Institut für Immunologie (Autor:in)
  • Stephen J Crocker - , University of Connecticut Health (Autor:in)
  • Alfonso Calvo - , Universidad de Navarra (Autor:in)
  • Asis Palazon - , CIC bioGUNE, Derio, Bizkaia, Spain. (Autor:in)
  • Renacer Group - , CIBER - Centro de Investigación Biomédica en Red (Autor:in)
  • Manuel Valiente - , CIBER - Centro de Investigación Biomédica en Red (Autor:in)

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.

Details

OriginalspracheEnglisch
Seitenumfang23
FachzeitschriftCancer discovery
Jahrgang15
Ausgabenummer1
PublikationsstatusElektronische Veröffentlichung vor Drucklegung - 2 Okt. 2024
Peer-Review-StatusJa

Externe IDs

unpaywall 10.1158/2159-8290.cd-24-0134

Schlagworte

Schlagwörter

  • Astrocytes/metabolism, Brain Neoplasms/secondary, Mice, Animals, Humans, CD8-Positive T-Lymphocytes/immunology, Tissue Inhibitor of Metalloproteinase-1/metabolism, Lymphocytes, Tumor-Infiltrating/immunology