Siglec-15 Expression in Gastric Carcinoma and Its Association With Clinicopathological Variables

Gastric cancer remains the fifth most common malignancy worldwide and is often diagnosed at advanced stages with limited treatment options. Although immunotherapy targeting the programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) has improved outcomes in several cancers, many patients exhibit resistance, necessitating alternative therapeutic strategies. Sialic acid-binding immunoglobulin-like lectin-15 (Siglec-15), a recently recognized immune suppressor, is overexpressed in tumor cells and tumor-associated macrophages (TAMs), and is largely absent from normal tissues, making it a promising immunotherapy target.

This tissue microarray (TMA) study retrospectively collected formalin-fixed paraffin-embedded (FFPE) tissue specimens from 2015 to 2019 for 77 gastric cancer patients from King Hussein Cancer Center. Siglec-15 expression patterns in tumor cells and TAMs were analyzed and compared with clinicopathological features and patient outcomes. Survival was assessed using Kaplan-Meier analysis.

Siglec-15 expression was detected in 50.7% of tumor samples and 36.4% of TAMs. Membranous expression was significantly associated with tumor differentiation, with higher expression observed in moderately differentiated tumors (P = 0.048), while cytoplasmic and TAM expression showed no significant associations with clinical variables. Although not statistically significant, positive Siglec-15 expression-both membranous and cytoplasmic-was associated with shorter median overall survival (cytoplasmic: 30.62 vs. 74.92 months, P = 0.1790; membranous: 39.44 vs. 66.07 months, P = 0.5761). Established prognostic indicators such as age, clinical stage, and pT stage were significantly associated with overall survival.

Siglec-15 is frequently expressed in gastric cancer and may contribute to immune evasion within the tumor microenvironment. Although no significant association with prognosis was found, its high expression underscores its potential as a novel immunotherapeutic target. Further studies are warranted to validate these findings and explore Siglec-15 clinical utility.