2. Academic Validation
  3. Barcoded viral tracing identifies immunosuppressive astrocyte-glioma interactions

Barcoded viral tracing identifies immunosuppressive astrocyte-glioma interactions

  • Nature. 2025 Jun 25. doi: 10.1038/s41586-025-09191-9.
Brian M Andersen # 1 2,  Camilo Faust Akl # 1 3,  Michael A Wheeler 1 4 5,  Zhaorong Li 1,  Martin Diebold 6,  Michael Kilian 1,  Joseph M Rone 1 5,  Aditya Misra 5 7 8,  Jessica E Kenison 1,  Joon-Hyuk Lee 1,  Hong-Gyun Lee 1,  Carolina M Polonio 1,  David Merrell 4,  Jakob H Weiss 4,  Lillie Godinez 1,  Gavin Piester 1,  Tomer Illouz 1,  Jessica J Ye 1,  Arianna Ghia 1,  Jazmin Martinez 1,  Elizabeth N Chung 1,  Lena Srun 1,  Daniel Farrenkopf 1,  Lucas E Flausino 1,  Anton M Schüle 1,  Liliana M Sanmarco 1,  Federico Giovannoni 1,  Luca Fehrenbacher 6,  Marc Charabati 1,  Cristina Gutiérrez-Vázquez 1,  Margaret M Cusick 8 9,  Prem S Prabhakar 8 9,  Connor C Bossi 8 9,  Emily Lapinskas 8 9,  Roni Nowarski 1 4 5,  Gad Getz 4 10,  Keith L Ligon 8 9,  Marco Prinz 6 11,  E Antonio Chiocca 12,  David A Reardon 13,  Francisco J Quintana 14 15 16
Affiliations

Affiliations

  • 1 Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 2 Department of Neurology, Veterans Affairs Medical Center, Harvard Medical School, Jamaica Plain, MA, USA.
  • 3 Faculty of Biology, University of Freiburg, Freiburg, Germany.
  • 4 Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 5 The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 6 Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 7 Harvard-MIT Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 8 Department of Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 9 Department of Pathology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 10 Department of Pathology and Krantz Family Center for Cancer Research, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
  • 11 Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany.
  • 12 Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 13 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 14 Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. fquintana@rics.bwh.harvard.edu.
  • 15 Broad Institute of MIT and Harvard, Cambridge, MA, USA. fquintana@rics.bwh.harvard.edu.
  • 16 The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. fquintana@rics.bwh.harvard.edu.
  • # Contributed equally.
PMID: 40562937 DOI: 10.1038/s41586-025-09191-9
Abstract

Glioblastoma (GBM) is the most lethal primary brain malignancy1. Immunosuppression in the GBM tumour microenvironment (TME) is an important barrier to immune-targeted therapies, but our understanding of the mechanisms of immune regulation in the GBM TME is limited2. Here we describe a viral barcode interaction-tracing approach3 to analyse TME cell-cell communication in GBM clinical samples and preclinical models at single-cell resolution. We combine it with single-cell and bulk RNA-sequencing analyses, human organotypic GBM cultures, in vivo cell-specific CRISPR-Cas9-driven genetic perturbations as well as human and mouse experimental systems to identify an annexin A1-formyl peptide receptor 1 (ANXA1-FPR1) bidirectional astrocyte-GBM communication pathway that limits tumour-specific immunity. FPR1 inhibits immunogenic Necroptosis in tumour cells, and ANXA1 suppresses NF-κB and inflammasome activation in astrocytes. ANXA1 expression in astrocytes and FPR1 expression in Cancer cells are associated with poor outcomes in individuals with GBM. The inactivation of astrocyte-glioma ANXA1-FPR1 signalling enhanced dendritic cell, T cell and macrophage responses, increasing infiltration by tumour-specific CD8+ T cells and limiting T cell exhaustion. In summary, we have developed a method to analyse TME cell-cell interactions at single-cell resolution in clinical samples and preclinical models, and used it to identify bidirectional astrocyte-GBM communication through ANXA1-FPR1 as a driver of immune evasion and tumour progression.

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