Site-specific differences in Nectin-4 expression and associated immune contexture in advanced urothelial carcinoma: implications for Nectin-4-targeted ADCs.
Journal
Therapeutic advances in medical oncology
Journal Volume
18
Start Page
Article number 17588359261463147
ISSN
1758-8340
Date Issued
2026
Author(s)
Wang, Chung-Chieh
Hsu, Chia-Lang
Wu, Shu-Cheng
Chueh, Shih-Chieh
Guo, Jhe-Cyuan
Chuang, Chien-Huai
Tsai, Yu-Chieh
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 (H-score 100-300) or Nectin-4 (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, = 0.005; Nectin-4 70.6% vs 50.0%, = 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%, = 0.017). Immune profiling revealed a relatively immune-depleted pattern in Nectin-4 versus Nectin-4 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.
Differences in a treatment-related protein (Nectin-4) and immune features between bladder and upper urinary tract urothelial cancers, and what this may mean for antibody–drug conjugate therapies Urothelial carcinoma is a type of cancer that can arise in different parts of the urinary system, most commonly in the bladder or the upper urinary tract (such as the kidney pelvis and ureter). Although these cancers are often grouped together, they may behave differently in terms of biology and response to treatment. In this study, we focused on a protein called Nectin-4, which is an important target for a newer class of cancer treatments called antibody–drug conjugates. We examined how Nectin-4 is expressed in tumor samples from patients with advanced urothelial carcinoma and compared differences between bladder and upper urinary tract cancers. We found that bladder cancers generally had higher levels of Nectin-4 than upper urinary tract cancers. We also observed that in some patients, Nectin-4 levels changed when comparing the original tumor to metastatic sites, and this change was more common in bladder cancer. In addition, we analyzed immune-related activity within the tumors. Tumors with high Nectin-4 levels tended to show a less active immune environment in bladder cancer, while this pattern was less clear in upper urinary tract cancer. These findings were consistent across independent external datasets. Overall, our results suggest that bladder and upper urinary tract urothelial cancers are biologically different in terms of Nectin-4 expression and immune features. These differences may be important for understanding how patients respond to Nectin-4–targeted treatments.
Subjects
Nectin-4 expression
advanced urothelial carcinoma
anatomic site differences
antibody–drug conjugates
immune contexture
Type
journal article