T-cell-targeted immunotherapy in neurofibromatosis type 2-related vestibular schwannoma: current evidence and future direction.

Neurofibromatosis type 2-related schwannomatosis is a rare tumour predisposition syndrome caused by loss-of-function pathogenic variants within the NF2 gene, which encodes the tumour suppressor protein merlin. This leads to development of benign tumours within the nervous system, most notably vestibular schwannomas that form on the vestibulocochlear (eighth cranial) nerve. Whilst the merlin-regulated molecular mechanisms in neoplastic Schwann cells that underlie vestibular schwannoma formation and growth are increasingly understood, the role of the tumour-immune microenvironment-particularly T-cells-in influencing vestibular schwannoma pathology and the clinical trajectory of disease remain understudied. In this review, we outline fundamental principles of T-cell immunobiology and anti-tumour immunity and examine their relevance to neurofibromatosis type-2-related schwannomatosis-associated vestibular schwannoma. We describe how spatial and transcriptomic profiling of tumour-infiltrating lymphocytes have revealed hallmarks of T-cell exhaustion and immunoevasion within vestibular schwannoma tumours and the existence of myriad immunosuppressive mechanisms within the vestibular schwannoma microenvironment-including immune checkpoint ligand expression, immunosuppressive cytokines, regulatory immune subsets and metabolic constraints. We also review the key remaining biological prerequisites, such as T-cell dynamics, T-cell functional state and T-cell spatial context within the tumour microenvironment, that must be addressed before advanced T-cell-based strategies can be rationally developed for vestibular schwannoma.