The inflammatory microenvironment in vestibular schwannoma

Abstract

Vestibular schwannomas are tumors arising from the vestibulocochlear nerve at the cerebellopontine angle. Their proximity to eloquent brainstem structures means that the pathology itself and the treatment thereof can be associated with significant morbidity. The vast majority of these tumors are sporadic, with the remainder arising as a result of the genetic syndrome Neurofibromatosis Type 2 or, more rarely, LZTR1-related schwannomatosis. The natural history of these tumors is extremely variable, with some tumors not displaying any evidence of growth, others demonstrating early, persistent growth and a small number growing following an extended period of indolence. Emerging evidence now suggests that far from representing Schwann cell proliferation only, the tumor microenvironment is complex, with inflammation proposed to play a key role in their growth. In this review, we provide an overview of this new evidence, including the role played by immune cell infiltration, the underlying molecular pathways involved, and biomarkers for detecting this inflammation in vivo. Given the limitations of current treatments, there is a pressing need for novel therapies to aid in the management of this condition, and we conclude by proposing areas for future research that could lead to the development of therapies targeted toward inflammation in vestibular schwannoma.

Keywords: biomarkers; inflammation; macrophages; neurofibromatosis type 2; vestibular schwannoma.

Fig. 1

Iba1+ macrophage abundance in growing vestibular schwannoma (VS). Representative serial MRI and Iba1-stained immunosections from a patient with a static VS (A) and a rapidly growing sporadic VS (B). Serial T2W imaging through the cerebellopontine angle at 0 months and 18 months demonstrates the differential growth rates between the two tumors and Iba1 immunostains (red, immunoperoxidase, ×10) demonstrate the high macrophagic infiltrates seen within the rapidly growing VS.

Fig. 2

Immune microenvironment in vestibular schwannoma (VS). Alongside the neoplastic Schwann cell population studies have shown that immune cells also contribute to the tumor microenvironment (TME) in VS. This immune cell population includes both B and T lymphocytes and a population of tumor-associated macrophages (TAMs). Circulating bone marrow-derived monocytes are thought to be the origin of these TAMs and previous studies have demonstrated a close association between the tumor vasculature and this intratumoral macrophage population in VS.^,, While recent studies have demonstrated upregulation of candidate cytokines, chemokines, and cellular adhesion molecules within sporadic VS tissue,^,,, the key chemoattractants that recruit circulating monocytes and drive their differentiation into macrophages are still under investigation. Extracellular matrix (ECM) components such as collagen and glycoprotein laminin are also a prominent feature of the TME in VS.^, The extent to which the ECM interacts with the immune cell population in driving VS progression has not been investigated, however, and should be a direction for future research. This figure was created under license using BioRender.com. https://biorender.com/

Fig. 3

Hypothesized inflammatory pathways implicated in vestibular schwannoma. Typically macrophages are polarized to an M1 phenotype by TLR (Toll-like receptor) ligands such as LPS (lipopolysaccharide), IFNγ (interferon-γ), or TNFα (tumor necrosis factor-α), secrete pro-inflammatory cytokines, and have anti-tumorigenic properties. Alternatively, these macrophages can be polarized to an M2 phenotype by GM-CSF (granulocyte-macrophage colony-stimulating factor), IL-12 (interleukin-12), and IL-14 (interleukin-14), secrete anti-inflammatory cytokines, and have pro-tumorigenic properties. These secreted cytokines bind to receptors on the cell surface of Schwann cells, initiate the transcription factor NF-κB (nuclear factor kappa-B) upregulating TNF-α, IL-1β (interleukin-1β), IL-6 (interleukin-6), COX-2 (cyclooxygenase-2), NLRP3 (NOD-like receptor protein 3), pro-IL1β (pro-interleukin1β), and IL-18 (interleukin-18). The cytoskeleton protein Merlin can act as a tumor suppressor by blocking the transcription of nuclear NF-κB. COX-2 production can be regulated by NF-κB and inhibitors of COX-2 such as aspirin reduce its activation. This figure was created under license using BioRender.com. https://biorender.com/

Fig. 4

[¹¹C]-(R)-PK11195 PET as a biomarker of intratumoral inflammation in vestibular schwannoma (VS). Representative imaging and histology from a patient with a static left-sided VS (A) and a growing right-sided VS (B) are shown. Specific binding of the TSPO PET tracer, [¹¹C]-(R)-PK11195, is demonstrably higher within the growing VS compared to the static tumor. Comparative immunohistochemistry (Iba1 red, immunoperoxidase) demonstrates that the source of this increased specific binding within the growing VS was an abundance of intratumoral Iba1+ macrophages.