Meningiomas in patients with neurofibromatosis type 2 predominantly comprise 'immunogenic subtype' tumours characterised by macrophage infiltration

Abstract

Although recent molecular analyses revealed that sporadic meningiomas have various genetic, epigenetic, and transcriptomic profiles, meningioma in patients with neurofibromatosis type 2 (NF2) have not been fully elucidated. This study investigated meningiomas' clinical, histological, and molecular characteristics in NF2 patients. A long-term retrospective follow-up (13.5 ± 5.5 years) study involving total 159 meningiomas in 37 patients with NF2 was performed. Their characteristics were assessed using immunohistochemistry (IHC), bulk-RNA sequencing, and copy number analysis. All variables of meningiomas in patients with NF2 were compared with those in 189 sporadic NF2-altered meningiomas in 189 patients. Most meningiomas in NF2 patients were stable, and the mean annual growth rate was 1.0 ± 1.8 cm³/year. Twenty-eight meningiomas (17.6%) in 25 patients (43.1%) were resected during the follow-up period. WHO grade I meningiomas in patients with NF2 were more frequent than in sporadic NF2-altered meningiomas (92.9% vs. 80.9%). Transcriptomic analysis for patients with NF2/sporadic NF2-altered WHO grade I meningiomas (n = 14 vs. 15, respectively) showed that tumours in NF2 patients still had a higher immune response and immune cell infiltration than sporadic NF2-altered meningiomas. Furthermore, RNA-seq/IHC-derived immunophenotyping corroborated this enhanced immune response by identifying myeloid cell infiltration, particularly in macrophages. Clinical, histological, and transcriptomic analyses of meningiomas in patients with NF2 demonstrated that meningiomas in NF2 patients showed less aggressive behaviour than sporadic NF2-altered meningiomas and elicited a marked immune response by identifying myeloid cell infiltration, particularly of macrophages.

Keywords: Immune infiltration; Meningioma; Neurofibromatosis type 2; Tumour microenvironment.

Fig. 1

Different clinical characteristics between meningioma in NF2 patients versus sporadic NF2-altered meningioma. A Representative images of meningiomas in NF2 patients and sporadic NF2-altered meningioma. B Pie chart of the anatomical location of the meningiomas. C Pie chart of the histological findings of the meningiomas. D The box plot shows the differences in the Ki-67 index of the meningiomas. E The box plot shows the differences in annual tumour growth rate between meningiomas in NF2 patients and operated meningiomas in NF2 patients

Fig. 2

Molecular characteristics of NF2-altered WHO grade I meningiomas (Meningioma in NF2 patients versus sporadic NF2-altered meningiomas). A Pie chart of the frequency of chromosome 22 q loss in the meningiomas. B Pie chart of the frequency of chromosome 1 p loss in the meningiomas. C The box plot shows the differences in the meningiomas’ NF2 expression (FPKM). D Unsupervised hierarchical clustering of genes revealed two molecular groups that mostly matched meningiomas in patients with NF2 and sporadic NF2-altered meningiomas E GSEA showed that the differentially expressed genes between NF2 patients’ and sporadic NF2-altered tumours were significantly overrepresented in signatures associated with ‘ALLOGRAFT REJECTION’, ‘INTERFERON GAMMA RESPONSE’, ‘COMPLEMENT’, and ‘INFLAMMATORY RESPONSE’. F Pathway analysis of differentially expressed genes revealed that the immune response-associated genes were the most significantly enriched transcripts in NF2 patients’ relative to sporadic NF2-altered tumours

Fig. 3

Immune infiltration and immune activity in NF2-altered meningiomas The RNA-seq–derived immune metrics from three methods including xCell²⁷, ESTIMATE²⁸, and CIBERSORT²⁶ was compared between meningiomas in NF2 patients and sporadic NF2-altered meningioma A ESTIMATE tumour purity, B ESTIMATE immune score, C xCell immune score, D CIBERSORT immune score, E xCell absolute value of each cell types, F xCell absolute value of myeloid. dc: Dendritic cells, adc: activated dendritic cells, cdc: Conventional dendritic cells, idc: Immature dendritic cells, pdc: Plasmcytoid dendrtic cells. G xCell absolute value of lymphoid

Fig. 4

Quantification of immune cell infiltration between NF2 patients’ and sporadic NF2-altered tumours. Immunohistochemistry was performed using whole slide sections for CD3, CD4, CD8, CD19, CD45, CD68, CD163, FOXP3, and Granzyme B. IHC was quantified as the average number of nuclei/cell positivity per high-power field (HPF) from five distinct regions within each meningioma using the colour deconvolution plugin in FIJI (A; CD45, B; CD68⁺, C; CD68⁺163⁻, D; CD68⁺163⁺, E; CD68⁺163⁻ macrophages/CD68⁺163⁺ macrophages, F; CD3, G; CD4, H; CD8, I; FOXP3, J; Granzyme B, K; CD19⁺). L Representative IHC/IF images with each antibody