Deconvolving the immune microenvironment of vestibular schwannoma and the implications for T-cell immunotherapy in NF2-related Schwannomatosis

Abstract

NF2-related Schwannomatosis (NF2 SWN) is a rare tumour predisposition syndrome whereby patients develop multiple central and peripheral nervous system tumours. The clinical hallmark of this syndrome is bilateral vestibular schwannoma (VS), but many patients also development multiple meningiomas and ependymomas. Together, these tumours cause various symptoms such as sensorineural hearing loss, impaired balance, facial palsy, seizures, and many more that severely impact the quality of life in these patients. NF2 SWN is currently incurable, and with the limited options for therapeutic interventions, there is an urgent need to identify novel targets to advance the treatment and management of NF2 SWN-related tumours. The aim of this thesis was to use high dimensional approaches to interrogate the spatial topology of NF2 SWN-related VS and identify novel immune-based targets for the application of immunotherapy. Hence, imaging mass cytometry was utilised to deconstruct the immune environments present in VS, where we demonstrate distinctive spatial networks that potentially regulate T-cell localisation and activity within the tumour microenvironment of VS. Next, this work was supplemented by suspension mass cytometry to define in-depth phenotypic states of CD8+ T-cells in VS, which illustrated that intratumoral VS T-cells largely consist of phenotypically exhausted T-cell subsets, characterised by upregulation of co-inhibitory receptors like PD-1, highlighting their amenability to immune checkpoint blockade interventions. Thus, the findings of this thesis support the implementation of immunotherapy-based interventions for the treatment of VS and NF2 SWN and provide rationale for the induction of preclinical testing of these targets in clinically relevant models.

Date of Award	4 Nov 2024
Original language	English
Awarding Institution	The University of Manchester
Supervisor	David Brough (Supervisor), Omar Pathmanaban (Supervisor), Pawel Paszek (Supervisor) & Kevin Couper (Supervisor)