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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Neibla Priego - , CIBER - Center for Biomedical Research Network (Author)
  • Ana de Pablos-Aragoneses - , Centro Nacional de Investigaciones Oncológicas (CNIO), New York, NY, United States. (Author)
  • Maria Perea-García - , CIBER - Center for Biomedical Research Network (Author)
  • Valentina Pieri - , San Raffaele Scientific Institute, Milano, Italy, Italy. (Author)
  • Carolina Hernandez-Oliver - , CIBER - Center for Biomedical Research Network (Author)
  • Laura Alvaro-Espinosa - , CIBER - Center for Biomedical Research Network (Author)
  • Andrea Rojas - , CIBER - Center for Biomedical Research Network (Author)
  • Oliva Sanchez - , CIBER - Center for Biomedical Research Network (Author)
  • Ariane Steindl - , Medical University of Vienna (Author)
  • Eduardo Caleiras - , CIBER - Center for Biomedical Research Network (Author)
  • Fernando Garcia - , CIBER - Center for Biomedical Research Network (Author)
  • Santiago Garcia-Martin - , CIBER - Center for Biomedical Research Network (Author)
  • Osvaldo Grana-Castro - , CIBER - Center for Biomedical Research Network (Author)
  • Sandra Garcia-Mulero - , University of Barcelona (Author)
  • Diego Serrano - , University of Navarra (Author)
  • Paloma Velasco-Beltran - , CIC bioGUNE, Derio, Bizkaia, Spain. (Author)
  • Borja Jimenez-Lasheras - , CIC bioGUNE, Derio, Bizkaia, Spain. (Author)
  • Leire Egia-Mendikute - , CIC bioGUNE, Derio, Bizkaia, Spain. (Author)
  • Luise Rupp - , Institute for Immunology (Author)
  • Antonia Stammberger - , Institute for Immunology (Author)
  • Matthias Meinhardt - , Institute of Pathology (Author)
  • Anas Chaachou-Charradi - , Vall d'Hebron University Hospital (Author)
  • Elena Martínez-Saez - , Vall d'Hebron University Hospital (Author)
  • Luca Bertero - , University of Turin (Author)
  • Paola Cassoni - , University of Turin (Author)
  • Luca Mangherini - , University of Turin (Author)
  • Alessia Pellerino - , Azienda Ospedaliera - Universitaria Città della Salute e della Scienza di Torino (Author)
  • Roberta Ruda - , Azienda Ospedaliera - Universitaria Città della Salute e della Scienza di Torino (Author)
  • Riccardo Soffietti - , Candiolo Cancer Institute FPO-IRCCS (Author)
  • Fatima Al-Shahrour - , CIBER - Center for Biomedical Research Network (Author)
  • Paul Saftig - , Kiel University (Author)
  • Rebeca Sanz-Pamplona - , IISA, Zaragoza, Spain. (Author)
  • Marc Schmitz - , Institute for Immunology (Author)
  • Stephen J Crocker - , University of Connecticut Health (Author)
  • Alfonso Calvo - , University of Navarra (Author)
  • Asis Palazon - , CIC bioGUNE, Derio, Bizkaia, Spain. (Author)
  • Renacer Group - , CIBER - Center for Biomedical Research Network (Author)
  • Manuel Valiente - , CIBER - Center for Biomedical Research Network (Author)

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 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, 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 TIMP1 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.

Details

Original languageEnglish
JournalCancer discovery
Publication statusE-pub ahead of print - 2 Oct 2024
Peer-reviewedYes

External IDs

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

Keywords