Fibrotic Response to Anti-Csf-1R Therapy Potentiates Glioblastoma Recurrence

Authors

Spencer S Watson
Anoek Zomer
Nadine Fournier
Joao Lourenco
Manfredo Quadroni
Agnieszka Chryplewicz
Sina Nassiri
Pauline Aubel
Simona Avanthay
Davide Croci
Erik Abels
Marike L D Broekman
Douglas Hanahan
Jason T Huse
Roy T Daniel
Monika E Hegi
Krisztian Homicsko
Giulia Cossu
Andreas F Hottinger
Johanna A Joyce

Publication Date

9-9-2024

Journal

Cancer Cell

DOI

10.1016/j.ccell.2024.08.012

PMID

39255775

Abstract

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.

Keywords

Glioblastoma, Animals, Humans, Mice, Neoplasm Recurrence, Local, Tumor Microenvironment, Fibrosis, Brain Neoplasms, Receptor, Macrophage Colony-Stimulating Factor, Cell Line, Tumor, Signal Transduction, Xenograft Model Antitumor Assays, Transforming Growth Factor beta

Published Open-Access

yes

Recommended Citation

Watson, Spencer S; Zomer, Anoek; Fournier, Nadine; et al., "Fibrotic Response to Anti-Csf-1R Therapy Potentiates Glioblastoma Recurrence" (2024). Faculty, Staff and Student Publications. 4527.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4527