Genomic and Immune Correlates of EZH2 Expression and Activity in Olfactory Neuroblastoma.

Abstract

Olfactory neuroblastoma (ONB) is a rare sinonasal malignancy with limited therapeutic options in the recurrent/metastatic setting; little is known regarding its responsiveness to immunotherapy. Inhibition of enhancer of zeste homolog 2 (EZH2) has been shown to improve T-cell-mediated killing and susceptibility to immune checkpoint inhibitors in a variety of cancers. We aimed to evaluate the expression and activity of EZH2 in ONB and its association with immune characteristics. We studied a cohort of 36 ONB real-world patient samples that underwent molecular profiling at a centralized lab (Caris Life Science). To infer EZH2 methyltransferase activity, we adopted an EZH2 gene repression signature (ERS) score: ONB samples were stratified into ERS-low and ERS-high subgroups, corresponding to high and low inferred EZH2 methyltransferase activity, respectively. Transcriptomic data were utilized to calculate the T-cell-inflamed (TCI) score and mitogen-activated protein kinase (MAPK) pathway activation score (MPAS). Tumor immune microenvironment composition was inferred from tumor-derived bulk RNA sequencing data. We analyzed immunologic differences between ERS-low and ERS-high ONB. In ERS-high ONB, we observed a higher expression of immune-related genes, a higher proportion of TCI tumors, and an enrichment in inflammatory pathways. ERS-high ONB also displayed increased macrophages, and to a lesser extent, B cells and CD8⁺ T cell infiltration in the tumor microenvironment. Also, ERS-high was associated with increased MPAS, potentially identifying ONB with increased susceptibility to MAPK inhibitors. These data were confirmed in an independent validation cohort using a publicly available dataset. Taken together, our data suggest that low EZH2 activity is associated with a more immunogenic microenvironment, paving the way for potential combinations of EZH2 inhibitors with checkpoint blockade in ONB.