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Targeting the CSF1/CSF1R Axis is a Potential Treatment Strategy for Malignant Meningiomas.

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.