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Published on: October 27, 2014
Fibrotic response to anti-CSF-1R therapy potentiates glioblastoma recurrence
Spencer S Watson1, Anoek Zomer2, Nadine Fournier3
1Department of Oncology, University of Lausanne, 1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, 1011 Lausanne, Switzerland; Agora Cancer Research Center Lausanne, 1011 Lausanne, Switzerland; Agora Cancer Centre, University Hospital Lausanne, 1011 Lausanne, Switzerland; Lundin Brain Tumour Centre, University Hospital Lausanne, 1011 Lausanne, Switzerland.
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.
Insights
Targeting brain tumor-associated immune cells with CSF-1R inhibitors can regress glioblastoma. However, fibrotic scars promote recurrence, suggesting combined therapies are needed for long-term survival.
Area of Science:
- Neuro-oncology
- Cancer Immunology
- Tumor Microenvironment Research
Background:
- Glioblastoma recurrence remains a significant challenge despite current treatments.
- CSF-1R inhibition shows promise in preclinical glioblastoma models by targeting tumor-associated macrophages and microglia.
- Recurrences after CSF-1R inhibition are linked to fibrotic scars, a common response to anti-glioma therapies.
Purpose of the Study:
- Investigate the role of fibrotic scars in glioblastoma recurrence after CSF-1R inhibition.
- Identify mechanisms driving fibrotic responses and their impact on tumor dormancy and immune evasion.
- Evaluate combinatorial therapies to overcome treatment-associated fibrosis and improve survival.
Main Methods:
- Preclinical glioblastoma models treated with CSF-1R inhibitors.
- Multi-omics analysis of the tumor microenvironment post-treatment.
- Histopathological and molecular characterization of fibrotic scars.
- Assessment of combinatorial inhibition of TGF-β signaling and neuroinflammation.
Main Results:
- Fibrotic scars were consistently observed in recurrent tumors following anti-glioma therapies.
- Fibrotic areas were identified as pro-tumor niches supporting glioma cell dormancy and immune suppression.
- Perivascular fibroblast-like cells, activated by TGF-β signaling and neuroinflammation, mediated fibrosis.
- Combinatorial inhibition of fibrosis-driving pathways significantly improved survival in preclinical models.
Conclusions:
- Fibrotic scarring is a critical mechanism of glioblastoma recurrence after CSF-1R inhibition.
- Targeting fibrotic pathways in combination with CSF-1R inhibitors offers a promising strategy to enhance therapeutic efficacy.
- Understanding the tumor microenvironment's role in treatment resistance is crucial for developing effective glioblastoma therapies.
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