Zielgerichtete Therapie gegen Tumor-assoziierte Makrophagen im Immun-Microenvironment von Meningeomen

Meningioma represents the most common primary brain malignancy in adults with a subset of tumors exhibiting aggressive clinical behavior. Immunotherapy might present a new treatment strategy but is highly dependent on the immunological composition of the tumor microenvironment. Our previous data have shown that tumor-associated macrophages (TAMs) make up the main immune cell population in meningiomas with a negative impact on patient outcome. In this study, we investigated whether TAMs from meningioma tissue can be reprogrammed to an immunologically active and tumoricidal phenotype.

CD11b+ sorted macrophages derived from tumor samples from > 40 patients including clinically aggressive meningiomas were treated with small molecule inhibitors targeting the colony-stimulating factor-1 receptor (CSF-1R). In a first analysis, the direct treatment response of patient-derived macrophages has been investigated by various techniques including flow cytometry and bulk RNA-sequencing of treated TAMs and further analysis of the macrophage-conditioned media after treatment. In addition, we studied the influence of CSF-1R-targeted macrophage treatment on the phenotype and functional activity of T cells to assess a potential indirect treatment response in the tumor microenvironment.

Our data revealed that CSF-1R-targeted treatment of CD11b+ TAMs induced significant changes in the protein and gene expression of macrophage polarization markers towards a more immunologically active state and a significantly higher metabolic nitric oxide production as another sign of immunological activation. Subsequent analysis of indirect effects on T cells showed not only a significantly increased expression of the T cell activation marker CD69+, but also a significantly increased tumor cell killing by autologous T cells after macrophage-targeted treatment.

Together these data suggest both a direct and indirect CSF-1R-targeted macrophage treatment response in the local tumor microenvironment and give first promising results on the efficacy of macrophage-targeted immunotherapy in human meningiomas.