NECTIN4 defines a subtype-dependent tumor state coupling enfortumab vedotin targetability to antitumor immunity in bladder cancer
Nishimura, K.; Maenosono, R.; Owari, T.; Sakamoto, M.; Nishino, T.; Hirosuna, K.; Tsujino, T.; Izumi-Tamura, T.; Yoshikawa, Y.; Azuma, M.; Inoue, S.; Kawachi, A.; Ishida, A.; Nishimori, K.; Mukohyama, J.; Shinohara, N.; Sakumoto, M.; Amisaki, M.; Okuyama, K.; Ishida, M.; Ajiro, M.; Hirose, Y.; Suzuki, Y.; Nishikawa, H.; Azuma, H.; Carvalho, F. L. F.; Kibel, A. S.; Jia, L.; Koyama, S.; Yoshino, T.; Komura, K.; Yoshimi, A.
Show abstract
NECTIN4 is the target of enfortumab vedotin (EV), but its biological role in bladder cancer (BC) and its relationship to EV plus PD-1 blockade remain unclear. Integrating clinical multi-omics, spatial and single-cell immune profiling, and experimental models, we identify NECTIN4 as a subtype-dependent determinant of tumor state and antitumor immunity. In basal BC cells, NECTIN4 suppressed inflammatory and mesenchymal programs. Consistently, NECTIN4-high basal/squamous muscle-invasive BCs showed favorable survival, higher checkpoint inhibitor response rates, and a coordinated CD8+ T cell-inflamed microenvironment with no comparable associations in luminal papillary tumors. In orthotopic models, murine Nectin4 promoted CD8+ T cell-dependent tumor control, whereas human NECTIN4 conferred EV sensitivity. EV also attenuated NECTIN4-dependent TIGIT binding. Conversely, NECTIN4-low models were preferentially sensitive to HDAC inhibition. NECTIN4 therefore couples antibody-drug conjugate targetability to a subtype-specific tumor-immune state permissive for checkpoint blockade, whereas the NECTIN4-low state defines a distinct inflammatory-mesenchymal state with an alternative therapeutic vulnerability.
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