Characterization of Somatostatin Receptor 2 Gene Expression and Immune Landscape in Sinonasal Malignancies

Abstract

Olfactory neuroblastoma (ONB), sinonasal undifferentiated carcinoma (SNUC), and sinonasal neuroendocrine carcinoma (SNEC) are rare malignancies arising from the sinonasal tract with limited therapeutic options. The expression of the somatostatin receptor 2 gene (SSTR2), which is expressed in other neuroendocrine neoplasms and is therapeutically actionable, has been reported in these tumors. Here, we analyzed SSTR2 gene expression and its associations with genomic features, established biomarkers predicting of immune response, and the tumor immune microenvironment in a cohort of ONB, SNUC, and SNEC tumor samples (26, 13, and 8 samples, respectively) from a real-world database. SSTR2 gene expression was high in neural-type ONB and low in basal-type ONB and in most of the SNUC and SNEC cases; there was no difference in expression between primary and metastatic tumors. The T cell-inflamed (TCI) score analysis classified 38.5% of SNUC cases as T cell-inflamed compared to only 3.9% of ONB and 0% of SNEC cases; 26.9% of ONB cases were classified as intermediate TCI; and SNEC had the lowest relative immune cell infiltration by deconvolution. In high SSTR2-expressing ONB, there was a higher proportion of infiltrating of Natural Killer cells and dendritic cells by deconvolution. Additionally, high SSTR2-expressing ONB was enriched for proliferation pathways, including E2F and Myc targets and G2M checkpoints. In conclusion, our findings delineate significant differences between these three types of sinonasal malignancies that were examined. In ONB, relative to SNUC and SNEC, the SSTR2 expression profile, combined with its immune profiles, indicates potential novel therapeutic strategies and combinations for this unmet clinical need. Conversely, the inflammatory microenvironment of SNUC may be targetable using immuno-oncologic therapies.

Keywords: RNA-Seq; exome sequencing; olfactory neuroblastoma; sinonasal neuroendocrine carcinoma; sinonasal undifferentiated carcinoma; somatostatin receptor 2; tumor biomarkers; tumor microenvironment.

Figure 1

(a) SSTR2 expression in transcripts per million (TPM) for the indicated tumor types (asterisks indicate statistical significance; * p < 0.05 and ** p < 0.01). (b) Oncoprint showing the prevalence of immune biomarkers (IHC-PD-L1 measured through a 22C3 antibody assay; TMB—high classification) and the prevalence of pathogenic mutations (pathogenic single-nucleotide variant/insertion–deletion) for each tumor type. Asterisks indicate statistical significance; * p < 0.05.

Figure 2

(a) Heatmap showing SSTR2 expression (transcripts per million: TPM), prevalence of T cell-inflamed subtypes, prevalence of immune biomarkers, and % immune infiltrate (derived from bulk RNA sequencing using quantTIseq) for indicated tumor types. (b) Heatmap showing correlation of immune cell fractions and T cell-inflamed score with SSTR2 expression level. Correlation and corresponding p-values are shown within heatmap. Asterisk indicates statistical significance; * p < 0.05, ** p < 0.01, *** p < 0.001, and **** p < 0.0001. Abbreviations: SSTR2—somatostatin receptor 2; TCI score—T cell-inflamed score; ns—non significant.

Figure 3

(a) Differentially expressed genes between high SSTR-expressing ONB vs. low SSTR2-expressing ONB. (b) Gene set enrichment analysis between high vs. low SSTR2-expressing ONB. (c) Heatmap depicting neural- and basal-associated genes. (d) SSTR2 expression compared between neural and basal ONB. Asterisks indicate statistical significance; ** p < 0.01. Abbreviations: ns, non statistically significant.