Comprehensive Profiling of Cell Surface Proteins in Testicular Germ Cell Tumors.

To characterize clinically actionable cell surface proteins in testicular germ cell tumors (GCT), we retrospectively analyzed archival formalin-fixed, paraffin-embedded orchiectomy specimens from 30 patients, including 11 with pure seminoma and 19 with mixed GCTs. Immunohistochemistry was performed for 21 surface antigens using an automated platform. Staining intensity (0 to 3+) and the percentage of positive tumor cells were used to derive H-scores (0-300). Expression was summarized by patient classification and histologic component; high expression was defined as H-score ≥100. Claudin-6 (CLDN6) was diffusely and strongly expressed, with H-score ≥100 in 100% of pure seminomas and 89.5% of mixed GCTs. At the component level, 100% of seminoma and 92.9% of embryonal carcinoma samples reached this threshold. Epidermal growth factor receptor (EGFR) showed high expression in 68.4% of mixed GCTs and 45.5% of pure seminomas, with most enrichment in teratoma components (73.3%, ≥100; mean H-score, 212). TROP2 was markedly upregulated in mixed GCTs (78.9%, ≥100; mean, 194.7), particularly in teratoma components (86.7%, ≥100). Nectin-4 and glycoprotein nonmetastatic melanoma B (GPNMB) were expressed in smaller but notable subsets, including teratoma and seminoma, whereas most remaining antigens, including CD19, DLL3, FOLR1, and BCMA, showed minimal or no expression. These findings demonstrate a distinct surface antigen landscape in testicular GCTs, with CLDN6, EGFR, and TROP2 emerging as leading candidates for further translational evaluation. The enrichment of these targets highlights antigenic heterogeneity within GCTs and supports further validation in appropriate disease settings, including metastatic, posttreatment, and relapsed or refractory disease. SIGNIFICANCE: Relapsed or refractory testicular GCT remains a clinical challenge with limited treatment options. We evaluated cell surface antigens of primary GCTs and identified CLDN6, EGFR, and TROP2 as candidate targets for antigen-directed approaches. These findings provide a rationale for future validation in metastatic and posttreatment disease settings.