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. [Display omitted] •Multi-omics profiling of the glioblastoma TME following immunotherapy treatment•Multiple modes of glioblastoma therapy trigger a fibrotic response•Post-treatment fibrotic niches promote tumor cell survival and recurrence•Inhibition of treatment-associated fibrosis improves efficacy of anti-CSF-1R therapy Watson et al. show that multiple modes of therapy-induced glioblastoma regression are associated with fibrosis, which promotes tumor cell survival. Using multi-omics analyses, they identify the signaling pathways related to immunotherapy-associated fibrosis and show that inhibition of this response improves survival in preclinical trials.