Site-specific differences in Nectin-4 expression and associated immune contexture in advanced urothelial carcinoma: implications for Nectin-4-targeted ADCs.

Authors

Fu-Jen Hsueh, Chung-Chieh Wang, Chia-Lang Hsu, Shu-Cheng Wu, Jhe-Cyuan Guo, Chien-Huai Chuang, Shih-Chieh Chueh, Yu-Chieh Tsai

Published in

Therapeutic advances in medical oncology. Volume 18. Pages 17588359261463147. Epub Jul 07, 2026.

Abstract

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.
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.
A retrospective cohort study.
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-4^High (H-score 100-300) or Nectin-4^Low (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.
Primary UBC tumors exhibited significantly higher Nectin-4 expression than UTUC tumors (median H-score 150.0 vs 95.0, p = 0.005; Nectin-4^High 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-4^High versus Nectin-4^Low tumors in UBC, whereas this pattern was less evident in UTUC. These findings were consistent with those from external transcriptomic datasets.
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.

PMID:
42422333
Bibliographic data and abstract were imported from PubMed on 09 Jul 2026.

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