P14.18.A SCHWANNOMAS DISPLAY CONSERVED CELLULAR STATES AND PREFERENTIAL MHC CLASS II ANTIGEN PRESENTATION ACROSS DIFFERENT GENETIC BACKGROUNDS AND ANATOMIC LOCATIONS

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Abstract BACKGROUND Despite being associated with molecular alterations in the NF2 gene, there is limited understanding of the gene expression programs that govern the behavior of schwannomas—both in sporadic cases and in patients with schwannoma predisposition syndromes—and how these programs relate to tumor anatomic location. MATERIAL AND METHODS We characterized the transcriptional heterogeneity of schwannomas across different genetic backgrounds and anatomic locations at single-cell resolution. Tumor samples from patients undergoing resection for symptomatic schwannoma were dissociated and processed for whole-transcriptome profiling using Smart-seq2. Our cohort included 22 schwannomas: 5 from schwannomatosis patients, 11 from neurofibromatosis type 2 (NF2) patients, and 6 sporadic tumors (3 post-radiation). Anatomically, 12 tumors were from cranial nerves (11 vestibular, 1 accessory), and 10 from spinal or peripheral nerves. RESULTS We profiled 11,373 cells, including 4,725 neoplastic cells and various non-neoplastic populations. Copy number alteration analysis revealed intratumoral polyclonality. Non-negative matrix factorization identified six conserved transcriptional metaprograms related to stress response, myelin production, antigen presentation, interferon signaling, glycolysis, and extracellular matrix remodeling. Notably, schwannomas exhibited a distinctive antigen presentation metaprogram, enriched for MHC class II genes (e.g., HLA-DRA, HLA-DRB1). Additionally, we observed a distinct interferon signaling program, which was conserved across most tumors but attenuated in vestibular schwannomas, indicating a potential mechanism of regional immune evasion. Comparison with pan-cancer data confirmed the relative uniqueness of these immune-related programs to schwannomas. CONCLUSION We provide a comprehensive single-cell transcriptomic analysis of schwannomas across genetic and anatomic contexts. Our findings reveal unique, conserved immune-related transcriptional programs, particularly involving antigen presentation and interferon signaling, which may contribute to tumor immune evasion and inform future immunotherapeutic strategies.

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