Therapeutic advances in medical oncology · 2026
Site-specific differences in Nectin-4 expression and associated immune contexture in advanced urothelial carcinoma: implications for Nectin-4-targeted ADCs.
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Hsueh Fu-Jen, Wang Chung-Chieh, Hsu Chia-Lang, Wu Shu-Cheng, Guo Jhe-Cyuan, Chuang Chien-Huai, Chueh Shih-Chieh, Tsai Yu-Chieh
Аннотация
BACKGROUND: Nectin-4 is a key therapeutic target of antibody-drug conjugates (ADCs) in advanced urothelial carcinoma (UC), but its expression patterns and underlying biology across anatomical sites remain poorly understood.
OBJECTIVES: This study aimed to elucidate Nectin-4-related features in bladder (urinary bladder carcinoma, UBC) and upper urinary tract (upper tract urothelial carcinoma, UTUC) through a multi-layered approach, including primary tumor characterization, paired primary-metastatic analyses, and immune transcriptomic profiling.
DESIGN: A retrospective cohort study.
METHODS: We retrospectively analyzed primary tumors from 139 patients with advanced UC, including 56 with paired metastatic specimens and 75 with sufficient primary tumor tissue for immune profiling. Membranous Nectin-4 expression was assessed by immunohistochemistry and categorized as Nectin-4High (H-score 100-300) or Nectin-4Low (0-99). Immune profiling was performed using the nCounter® PanCancer Immune Profiling Panel (NanoString Technologies). External transcriptomic datasets (UBC: TCGA-BLCA; UTUC: GSE244957) were used to assess the consistency of immune profiling results.
RESULTS: Primary UBC tumors exhibited significantly higher Nectin-4 expression than UTUC tumors (median H-score 150.0 vs 95.0, p = 0.005; Nectin-4High 70.6% vs 50.0%, p = 0.018). Among paired specimens, 33.9% (19/56) showed primary-metastatic changes in Nectin-4 status, which occurred more frequently in UBC than in UTUC (52.2% vs 21.2%, p = 0.017). Immune profiling revealed a relatively immune-depleted pattern in Nectin-4High versus Nectin-4Low tumors in UBC, whereas this pattern was less evident in UTUC. These findings were consistent with those from external transcriptomic datasets.
CONCLUSION: UBC and UTUC demonstrate distinct Nectin-4 expression patterns and associated immune contexture, highlighting the biological heterogeneity of Nectin-4 in advanced UC. Further prospective studies are warranted to validate these findings and clarify their clinical implications.
OBJECTIVES: This study aimed to elucidate Nectin-4-related features in bladder (urinary bladder carcinoma, UBC) and upper urinary tract (upper tract urothelial carcinoma, UTUC) through a multi-layered approach, including primary tumor characterization, paired primary-metastatic analyses, and immune transcriptomic profiling.
DESIGN: A retrospective cohort study.
METHODS: We retrospectively analyzed primary tumors from 139 patients with advanced UC, including 56 with paired metastatic specimens and 75 with sufficient primary tumor tissue for immune profiling. Membranous Nectin-4 expression was assessed by immunohistochemistry and categorized as Nectin-4High (H-score 100-300) or Nectin-4Low (0-99). Immune profiling was performed using the nCounter® PanCancer Immune Profiling Panel (NanoString Technologies). External transcriptomic datasets (UBC: TCGA-BLCA; UTUC: GSE244957) were used to assess the consistency of immune profiling results.
RESULTS: Primary UBC tumors exhibited significantly higher Nectin-4 expression than UTUC tumors (median H-score 150.0 vs 95.0, p = 0.005; Nectin-4High 70.6% vs 50.0%, p = 0.018). Among paired specimens, 33.9% (19/56) showed primary-metastatic changes in Nectin-4 status, which occurred more frequently in UBC than in UTUC (52.2% vs 21.2%, p = 0.017). Immune profiling revealed a relatively immune-depleted pattern in Nectin-4High versus Nectin-4Low tumors in UBC, whereas this pattern was less evident in UTUC. These findings were consistent with those from external transcriptomic datasets.
CONCLUSION: UBC and UTUC demonstrate distinct Nectin-4 expression patterns and associated immune contexture, highlighting the biological heterogeneity of Nectin-4 in advanced UC. Further prospective studies are warranted to validate these findings and clarify their clinical implications.