Fibrotic response to anti-CSF-1R therapy potentiates glioblastoma recurrence
Glioblastoma recurrence is currently inevitable despite extensive standard-of-care treatment. In preclinical studies, an alternative strategy of targeting tumor-associated macrophages and microglia through CSF-1R inhibition was previously found to regress established tumors and significantly increase overall survival. However, recurrences developed in ∼50% of mice in long-term studies, which were consistently associated with fibrotic scars. This fibrotic response is observed following multiple anti-glioma therapies in different preclinical models herein and in patient recurrence samples. Multi-omics analyses of the post-treatment tumor microenvironment identified fibrotic areas as pro-tumor survival niches that encapsulated surviving glioma cells, promoted dormancy, and inhibited immune surveillance. The fibrotic treatment response was mediated by perivascular-derived fibroblast-like cells via activation by transforming growth factor β (TGF-β) signaling and neuroinflammation. Concordantly, combinatorial inhibition of these pathways inhibited treatment-associated fibrosis, and significantly improved survival in preclinical trials of anti-colony-stimulating factor-1 receptor (CSF-1R) therapy.
Authors
- Andreas Felix Hottinger (ORCID: https://orcid.org/0000-0001-7098-9414)
- Erik R. Abels (ORCID: https://orcid.org/0000-0003-0146-3501)
- Agnieszka Chryplewicz (ORCID: https://orcid.org/0000-0003-0253-1166)
- Douglas Hanahan (ORCID: https://orcid.org/0000-0002-0883-5251)
- Johanna A. Joyce (ORCID: https://orcid.org/0000-0002-6332-2598)
- Giulia Cossu (ORCID: https://orcid.org/0000-0003-0913-8965)
- Sina Nassiri (ORCID: https://orcid.org/0000-0003-1274-8123)
- Anoek Zomer (ORCID: https://orcid.org/0000-0001-7209-6476)
- Jason T. Huse (ORCID: https://orcid.org/0000-0003-4514-0640)
- João Lourenço (ORCID: https://orcid.org/0000-0001-6549-5209)
- Pauline Aubel
- Monika E. Hegi (ORCID: https://orcid.org/0000-0003-0855-6495)
- Krisztián Homicskó (ORCID: https://orcid.org/0000-0003-0912-6198)
- Manfredo Quadroni (ORCID: https://orcid.org/0000-0002-2720-4084)
- Nadine Fournier (ORCID: https://orcid.org/0000-0002-9347-7929)
- Marike L. D. Broekman (ORCID: https://orcid.org/0000-0002-0226-0119)
- Roy Thomas Daniel (ORCID: https://orcid.org/0000-0002-7079-9837)
- Spencer S. Watson (ORCID: https://orcid.org/0000-0002-5583-1544)
- Davide Croci (ORCID: https://orcid.org/0000-0001-5212-1291)
- Simona Avanthay (ORCID: https://orcid.org/0000-0001-8142-7919)
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- Leiden University Medical Center (NL)
- Medisch Centrum Haaglanden (NL)
- Ludwig Cancer Research (CH)
- Swiss Cancer Center Léman (CH)
- École Polytechnique Fédérale de Lausanne (CH)
- University of Lausanne (CH)
Publication Details
- Journal
- Cancer Cell
- Published
- 2024-09-01
- DOI
- https://doi.org/10.1016/j.ccell.2024.08.012
- Citations
- 61
- Primary Topic
- Glioma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 26.71
Funders
- Ludwig Institute for Cancer Research
- Brain Tumour Charity
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Krebsliga Schweiz
- Université de Lausanne