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

## TL;DR

This study explores how EZH2 activity in olfactory neuroblastoma relates to immune responses, suggesting that EZH2 inhibitors could improve immunotherapy outcomes.

## Contribution

The study identifies a link between EZH2 activity and immune characteristics in olfactory neuroblastoma, suggesting new therapeutic strategies.

## Key findings

- ERS-high tumors showed higher immune gene expression and inflammatory pathways.
- ERS-high tumors had increased macrophage and CD8+ T cell infiltration.
- ERS-high tumors displayed increased MAPK pathway activation, suggesting potential for MAPK inhibitors.

## 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.