Alternatively activated macrophages are associated with faster growth rate in vestibular schwannoma

The variability in vestibular schwannoma growth rates greatly complicates clinical treatment. Management options are limited to radiological observation, surgery, radiotherapy and, in specific cases, bevacizumab therapy. As such, there is a pressing requirement for growth restricting drugs for vestibular schwannoma. This study explored potential predictors of vestibular schwannoma growth in depth, highlighting differences between static and growing vestibular schwannoma to identify potential therapeutic targets. High-dimensional imaging was used to characterize the tumour micro-environment of four static and five growing vestibular schwannoma (indicated by volumetric change < 20% or ≥ 20% per year, respectively). Single-cell spatial information and protein expression data from a panel of 35 tumour immune-targeted antibodies identified specific cell populations, their expression profiles and their spatial localization within the tumour micro-environment. Growing vestibular schwannoma contained significantly more proliferative and non-proliferative alternatively activated tumour-associated macrophages per millimetre square compared with static vestibular schwannoma. Furthermore, two additional proliferative cell types were identified in growing and static vestibular schwannoma: transitioning monocytes and programmed cell death ligand 1 (PD-L1+) Schwann cells. In agreement, growing vestibular schwannoma was characterized by a tumour micro-environment composed of immune-enriched, proliferative neighbourhoods, whereas static vestibular schwannoma were composed of tumour-enriched, non-proliferative neighbourhoods. Finally, classically activated macrophages significantly colocalized with alternatively activated macrophages in static vestibular schwannoma, but this sequestration was reduced in growing vestibular schwannoma. This study provides a novel, spatial characterization of the immune landscape in growing vestibular schwannoma, whilst highlighting the need for new therapeutic targets that modulate the tumour immune micro-environment.