Barcoded viral tracing identifies immunosuppressive astrocyte-glioma interactions PMID: 40562937

ADC Targets in Oncology

2026-04-10

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

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. [email protected].
15. Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
16. The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. [email protected].
# Contributed equally.

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.