TIMP1 Mediates Astrocyte-Dependent Local Immunosuppression in Brain Metastasis Acting on Infiltrating CD8+ T Cells
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.
Authors
- Eduardo J. Caleiras (ORCID: https://orcid.org/0000-0001-8768-3630)
- Ana de Pablos-Aragoneses (ORCID: https://orcid.org/0000-0001-9028-0576)
- Luca Mangherini (ORCID: https://orcid.org/0000-0001-8675-525X)
- Valentina Pieri (ORCID: https://orcid.org/0000-0001-9244-3834)
- Laura Álvaro‐Espinosa (ORCID: https://orcid.org/0000-0002-1036-8154)
- Alfonso Calvo (ORCID: https://orcid.org/0000-0003-4074-4242)
- Ariane Steindl (ORCID: https://orcid.org/0000-0002-5839-8301)
- Stephen J. Crocker (ORCID: https://orcid.org/0000-0003-4529-1385)
- Asís Palazón (ORCID: https://orcid.org/0000-0002-7172-7229)
- Luca Bertero (ORCID: https://orcid.org/0000-0001-9887-7668)
- Fátima Al‐Shahrour (ORCID: https://orcid.org/0000-0003-2373-769X)
- Paul Säftig (ORCID: https://orcid.org/0000-0003-2637-7052)
- Neibla Priego (ORCID: https://orcid.org/0000-0002-2587-0104)
- Paola Cassoni (ORCID: https://orcid.org/0000-0003-1977-7410)
- María Perea-García
- Matthias Meinhardt (ORCID: https://orcid.org/0000-0001-5775-5365)
- Manuel Valiente (ORCID: https://orcid.org/0000-0002-0647-7542)
- Leire Egia‐Mendikute (ORCID: https://orcid.org/0000-0002-6435-1219)
- Borja Jiménez-Lasheras (ORCID: https://orcid.org/0000-0002-1181-7492)
- Sandra García‐Mulero (ORCID: https://orcid.org/0000-0003-4931-1267)
- Rebeca Sanz‐Pamplona (ORCID: https://orcid.org/0000-0002-2187-3527)
- Anas Chaachou-Charradi (ORCID: https://orcid.org/0000-0002-9085-5314)
- Diego Serrano (ORCID: https://orcid.org/0000-0002-3729-9195)
- Carolina Hernández-Oliver (ORCID: https://orcid.org/0000-0002-5613-7140)
- Elena Martínez‐Sáez (ORCID: https://orcid.org/0000-0001-6004-5364)
- Santiago García‐Martín (ORCID: https://orcid.org/0000-0002-4540-9446)
- Osvaldo Graña‐Castro (ORCID: https://orcid.org/0000-0003-1615-4242)
- Marc Schmitz (ORCID: https://orcid.org/0000-0003-3417-6736)
- Luise Rupp (ORCID: https://orcid.org/0000-0002-6610-326X)
- Alessia Pellerino (ORCID: https://orcid.org/0000-0003-3243-0059)
- Riccardo Soffietti (ORCID: https://orcid.org/0000-0002-9204-7038)
- Paloma Velasco-Beltrán (ORCID: https://orcid.org/0000-0001-9686-5903)
- Roberta Rudà (ORCID: https://orcid.org/0000-0001-9134-1537)
- Fernando Garcı́a (ORCID: https://orcid.org/0000-0003-3888-4326)
- Antonia Stammberger (ORCID: https://orcid.org/0009-0005-1280-967X)
- RENACER Group
- Andrea Rojas (ORCID: https://orcid.org/0000-0003-4141-9118)
- Oliva Sánchez
Institutions
- Ikerbasque (ES)
- University of Connecticut (US)
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- Christian-Albrechts-Universität zu Kiel (DE)
- Fundacion Agencia Aragonesa para la Investigacion y el Desarrollo (ES)
- Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- Spanish National Cancer Research Centre (ES)
- Ajuntament de L’Hospitalet (ES)
- Institut Català d'Oncologia (ES)
- National Center for Tumor Diseases (DE)
- CIC bioGUNE (ES)
- Neuroscience Institute (IT)
- Vall d'Hebron Hospital Universitari (ES)
- Candiolo Cancer Institute (IT)
- Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (ES)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- University Hospital Carl Gustav Carus (DE)
- University of Turin (IT)
- UConn Health (US)
- Universidad de Navarra (ES)
Publication Details
- Journal
- Cancer Discovery
- Published
- 2024-10-02
- DOI
- https://doi.org/10.1158/2159-8290.cd-24-0134
- Citations
- 25
- Primary Topic
- Brain Metastases and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 10.47
Funders
- Cancer Research Institute
- European Molecular Biology Organization
- Fundación Ramón Areces
- Fundació la Marató de TV3
- “la Caixa” Foundation
- Ministerio de Ciencia, Innovación y Universidades
- European Commission
- Bundesministerium für Bildung und Forschung
- Fundación Científica Asociación Española Contra el Cáncer
- Eusko Jaurlaritza
- Ministerio de Ciencia e Innovación
- Centro Nacional de Investigaciones Cardiovasculares
- Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España
- National Institutes of Health
- Horizon 2020 Framework Programme
- Instituto de Salud Carlos III
- HORIZON EUROPE European Research Council