# Small Extracellular Vesicles Derived from NF2-Associated Schwannoma Cells Modulate Tumor Progression and Immunity via HSP90

## TL;DR

This study shows that small extracellular vesicles from NF2-associated schwannoma cells promote tumor growth and immune suppression by using HSP90 to influence cell signaling.

## Contribution

The novel finding is that HSP90 in sEVs from NF2 tumors regulates AKT/ERK pathways and MDSC conversion, offering new therapeutic insights.

## Key findings

- NF2-EVs induce monocytes to become MDSC-like cells with immune-suppressive functions.
- HSP90 in NF2-EVs regulates AKT/p-AKT and ERK/p-ERK pathways to promote tumor cell proliferation.
- Knocking down HSP90 reduces the ability of NF2-EVs to convert monocytes and promote tumor growth.

## Abstract

Small extracellular vesicles (sEVs) derived from NF2-associated schwannomas (NF2-EVs) express CD9 and CD81, with a size distribution ranging from 50 to 200 nm. NF2-EVs can induce the phenotypic transformation of CD14+ monocytes into MDSC cells. NF2-EVs-induced MDSC cells show increased expression of ARG1, iNOS, and BAFF, along with heightened secretion of IL-10, TNFα, MIP-1α, G-CSF, IL-8, and IL-6. Simultaneously, they produce a large amount of ROS and are able to inhibit the proliferation of autologous T cells. Additionally, NF2-EVs promote the proliferation of NF2 schwannoma cells. NF2-EVs highly express HSP90 and can regulate AKT/p-AKT and ERK/p-ERK through HSP90, thereby affecting cell proliferation and promoting the conversion of monocytes to MDSCs, which mediates immune suppression.

In-depth exploration of tumor immune suppression mechanisms may provide new therapeutic options for NF2-associated tumors. In this study, we found that sEVs secreted by NF2-associated schwannomas (NF2-EVs) facilitate the conversion of CD14+ monocytes into an MDSC-like phenotype, showcasing MDSC-like inhibitory functions. Moreover, these NF2-EVs are capable of enhancing tumor cell proliferation. Through proteomic analysis and subsequent validation of the NF2-EVs, we identified elevated levels of HSP90. When we knocked down HSP90 expression in tumor cells, the sEVs secreted showed diminished capacity to convert monocytes into MDSCs and a reduced ability to promote tumor cell proliferation. Conversely, sEVs secreted by tumor cells that overexpress HSP90 displayed the opposite effects. Further mechanistic studies revealed that HSP90 could influence the expression of AKT/p-AKT and ERK/p-ERK. Our results suggest that NF2 tumor cells could regulate the AKT/p-AKT and ERK/p-ERK pathways to promote tumor cell proliferation and the formation of an immunosuppressive microenvironment by secreting sEVs’ HSP90, offering valuable insights into the involvement of HSP90 in exosome-mediated communication within the context of NF2-related schwannomatosis (NF2-SWN). This information has the potential to inform the design of effective immunotherapeutic protocols and offer new treatment options for NF2-SWN patients.