Tumour neoantigen repertoire prediction in malignant peripheral nerve sheath tumours define private and public targets for immunotherapy

Malignant peripheral nerve sheath tumours (MPNSTs) are high grade soft-tissue sarcomas with an unmet need for novel therapies. Tumour antigen-based approaches, including neoantigen and tumour-associated antigen (TAA) directed therapies, offer potential opportunities for immunotherapy. Here, we integrated public domain tumour DNA and RNA sequencing data with in-silico prediction to systematically characterise the (neo)antigenic landscape of MPNST. We stratified the predictions across the two known sub-groups of MPNST, those associated without and with Polycomb Repressor Complex 2 (PRC2) loss of function variants (PRC2-Loss). Using computational pipelines including pVACtools, we identified high-confidence neoantigens based on pMHC affinity derived from somatic mutations and gene fusions, as well as recurrently overexpressed cell-surface TAAs. All predicted neoantigens were private to individual MPNST cases, with different neoantigens across both tumour subtypes. PRC2-Loss tumours showed reduced immune infiltration with downregulation of antigen processing and presentation pathways compared to PRC2-WT, confirming intrinsic constraints to effective neoantigen-directed immune priming. Moreover, PRC2-Loss MPNSTs demonstrated recurrent copy number driven overexpression of cell surface TAAs (chromosome 8), providing alternative immunotherapeutic targets that are pMHC independent. These findings confirm a PRC2-independent private immuno-antigenic peptide repertoire with an immune resistant MPNST microenvironment in PRC-Loss. These data provide further impetus for rational development of complementary immune based treatment strategies, including personalised neoantigen vaccines and cell surface protein TAA-directed therapies dependent on PRC2 status.