Targeting the CSF1/CSF1R axis is a potential treatment strategy for malignant meningiomas

Abstract

Background Malignant meningiomas are fatal and lack effective therapy. As M2 macrophages are the most prevalent immune cell type in human meningiomas, we hypothesized that normalizing this immunosuppressive population would be an effective treatment strategy. Methods We used CIBERSORTX to examine the proportions of 22 immune subsets in human meningiomas. We targeted the colony stimulating factor 1 (CSF1) or CSF1 receptor (CSF1R) axis, an important regulator of macrophage phenotype, using monoclonal antibodies (mAbs) in a novel immunocompetent murine model (MGS1) for malignant meningioma. RNA-seq was performed to identify changes in gene expression in the tumor microenvironment. Mass cytometry was used to delineate changes in immune subsets after treatment. We measured patients’ plasma CSF1 levels using ELISA and CSF1R expression using multiplex quantitative immunofluorescence in a human meningioma tissue microarray. Results Human meningiomas are heavily enriched for immunosuppressive myeloid cells. MGS1 recapitulates the tumor microenvironment of human meningiomas, including an abundance of myeloid cells, a paucity of infiltrating T cells, and low programmed-death ligand 1 (PD-L1) expression. Treatment of murine meningiomas with anti-CSF1/CSF1R, but not programmed cell death receptor 1 (PD-1), mAbs abrogate tumor growth. RNA-seq and mass cytometry analyses reveal a myeloid cell reprogramming with limited effect on T cells in the tumor microenvironment. CSF1 plasma levels are significantly elevated in human patients and CSF1R is highly expressed on CD163 + macrophages within the human tumor microenvironment. Conclusion Our findings suggests that anti-CSF1/CSF1R antibody treatment may be an effective normalization cancer immunotherapy for malignant meningiomas.

Phase 2 study of pembrolizumab in patients with recurrent and residual high-grade meningiomas

“…Recent studies suggest that targeting the immune microenvironment may be a promising strategy for meningiomas [6][7][8][9][10][11][12] . Genomic-characterization studies suggest that a subset of highgrade meningiomas possess a high somatic mutation burden 9 .…”

“…We found a decrease in CD4+ and CD8+ T cells, an increase in the number of FOXP3-expressing immunoregulatory (Treg) cells, and an increase in programmed deathligand-1 (PD-L1) expression on tumor cells, compared with grade-1 meningiomas 14 . Others have identified that the presence of immunosuppressive myeloid cells in high-grade meningioma 11,12 , linked PD-L1/PD-L2 expression with worse outcomes 10,12 , and found enrichment of PD-1/PD-L1 signaling in malignant meningiomas by single-cell RNA sequencing 11 .…”

Integrated phospho-proteogenomic and single-cell transcriptomic analysis of meningiomas establishes robust subtyping and reveals subtype-specific immune invasion

“…Controversially, elevated CSF1 expression levels have been associated with an unfavorable outcome in various tumor diseases 30–33 . Along these lines, a recent study found elevated levels of CSF1 in the plasma of meningioma patients, a correlation of CSF1 expression and an increased number of infiltrating macrophages of an anti-inflammatory phenotype, and a beneficial effect of CSF1/CSF1R targeting antibody treatment in a meningioma mouse model 34 .…”

Mouse Models in Meningioma Research: A Systematic Review

“…Mechanisms of meningioma progression were confirmed using later models, wherein Nf2 inactivation in synergy with homozygous or heterozygous Cdkn2ab deletions led to increased meningioma frequency and induced grade II and III meningiomas, thus representing a reliable atypical or anaplastic model that mimics the human pathology [59]. These models also offer the possibility of producing meningioma cell lines from mouse tumors and syngeneic orthotopic allografts to immunocompetent wildtype mice, which represent the closest models of sporadic malignant meningiomas [75].…”