Multimodal Characterization of the Meningioma Immune Landscape Reveals a Rich Microenvironment and Correlations with Tumor Biology

Introduction: Clinical outcomes for meningioma remain heterogeneous, with few effective treatment modalities for aggressive or recurrent tumors. Along with genomic alterations, immune populations within the meningioma microenvironment may also affect tumor fate. However, the constituents of the meningioma microenvironment and their relationship to tumor phenotype remain poorly understood.

Methods: We performed multi-modal high-resolution characterization on surgically resected samples from both the transcriptomic and proteomic perspectives to profile the meningioma immune landscape. Institutional and publicly available meningioma samples were assessed, including 24 with mass cytometry (CyTOF, 102,498 cells), 24 with single-cell RNA sequencing (115,586 cells), 1437 with bulk RNA sequencing, and 1129 with DNA methylation profiling. Paired-blood samples were also collected for a subset of meningiomas to compare immune compartments.

Results: While there were relative differences in the proportion of leukocytes within meningiomas, a robust immune compartment was detected in all profiled tumors. Immune cells comprised almost half of all cell populations per tumor: immune infiltrates dominated compared to tumor cells in low-grade meningiomas, with the opposite phenomenon was seen in high-grade meningiomas. The majority of intratumoral leukocytes were macrophages (~70%), generally polarized to a pro-inflammatory state, followed by T cells (~20%) and natural killer cells. This immune pattern was distinct from systemic compartments, where lymphocytes, especially T cells, dominated. High-grade, recurrent, and radiated meningiomas had a significant decrease in certain macrophage populations compared to low-grade, untreated, and non-radiated tumors. The differentiation state of immune cells further varied. In high-grade meningiomas, T cells were less differentiated compared with low-grade meningiomas. Further, in recurrent and metastatic meningiomas, T cells, macrophages, and tumor cells shifted to less differentiated states.

Conclusion : Though meningiomas continue to demonstrate cellular and clinical heterogeneity, the presence of a significant immune compartment highlights the potential for immune-modulatory therapeutics for these tumors.