Fibrotic response to anti-CSF-1R therapy potentiates glioblastoma recurrence
Spencer S Watson 1, Anoek Zomer 2, Nadine Fournier 3, Joao Lourenco 3, Manfredo Quadroni 4, Agnieszka Chryplewicz 5, Sina Nassiri 3, Pauline Aubel 1, Simona Avanthay 2, Davide Croci 2, Erik Abels 6, Marike L D Broekman 6, Douglas Hanahan 7, Jason T Huse 8, Roy T Daniel 9, Monika E Hegi 10, Krisztian Homicsko 11, Giulia Cossu 12, Andreas F Hottinger 13, Johanna A Joyce 14
. 2024 Sep 9;42(9):1507-1527.e11.
doi: 10.1016/j.ccell.2024.08.012.
- PMID: 39255775
- DOI: 10.1016/j.ccell.2024.08.012
Free article
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.