Genomic and Immune Profiling of Rare Non-Squamous Sinonasal Tumors.

e18008 Background: Sinonasal tumors (SNT) are rare tumors and make up less than 3% of all head and neck malignancies. The majority of SNTs have squamous cell histology and less common histologies remain understudied. We present a comprehensive analysis of genomic and immune profiles of rare SNTs that can help identify avenues for prognostic biomarkers and future targeted treatments. Methods: Non-squamous SNT samples (n =124) were profiled through Next Generation Sequencing (NGS) of DNA (592-genes; NextSeq or WES; NovaSeq) and RNA (WTS; NovaSeq) at Caris Life Sciences (Phoenix, AZ). Centralized pathology review was carried out to confirm histological subtypes. PD-L1 expression was tested by IHC (22c3, positive (+) >=1%; SP142, positive (2+)/ >=5%). Deficient mismatch repair/microsatellite instability (dMMR/MSI-H) was accessed by IHC/NGS. Immune cell fraction of the tumor microenvironment (TME) was estimated by quanTIseq, and gene expression profiles (transcript per million, TPM) were analyzed for transcriptional signatures predictive of response to immunotherapy. Mann-Whitney U and ChiSquare/Fisher-Exact tests were applied where appropriate, with p-values adjusted for multiple comparisons. Results: Non-squamous SNT samples included 35.5% (n = 44) adenoid cystic (ACC), 19.4% (n = 24) adenocarcinoma (AD), 10.5% (n = 13) undifferentiated carcinomas (SNUC), and 34.6% (n = 43) Esthesio/Olfactory Neuroblastomas (ENB). Notably, molecular features associated with each histological subtype are reported in the table. Furthermore, analysis of the inferred immune infiltrates showed that ENB had significantly higher fractions of NK cells (ACC: 5.6% vs AD: 4.6% vs SNUC: 4.4% vs ENB:10.5%, p <0.00001), CD8 T cells (0.1% vs 0.88% vs 0.22% vs 1%, p < 0.0001), CD4 T cells (0.4% vs 1.9% vs 0.03% vs 3.6%, p < 0.00001) and dendritic cells (4.5% vs 3.4% vs 2.6% vs 7.3%, p<0.00001) compared to the other sinonasal tumors. M1 macrophage (ACC: 2.6% vs AD: 1.9% vs SNUC: 1.1% vs ENB: 1.1%, p = 0.047) and Treg fractions (ACC: 2.0% vs AD: 1.6% vs SNUC: 1.2% vs ENB: 0.6%, p<0.00001) were significantly higher in ACC. There was also significantly increased expression of immune checkpoint genes in ENB compared to AD ( PD-1: 0.8 vs 0.5 TPM, p = 0.022) and in ENB compared to ACC ( HAVCR2: 3.4 vs 2.9 TPM, p = 0.047). Conclusions: To our knowledge, this is the largest study characterizing the genomic and immune alterations in non-squamous SNTs. Our findings offer potential for future targeted and immune therapeutic applications in these rare diseases. [Table: see text]