A tumor-cell MHC-II program is associated with checkpoint-blockade outcomes across stages of bladder cancer

Bellmunt, J.; Xie, Y.; Gomez Munoz, M.; Kukreja, S.; Walker, S.; He, R.; Li, R.; Qiu, X.; Zhang, T.; Rodriguez, P.; Garcia Gonzalez, D.; Epstein, I.; Parera, J.; Juanpere, N.; Lorenzo, M.; Buisan, O.; Senserrich, J.; Servian, P.; Silva, T.; Brown, M.; Cabrera, C.; Cejas, P.; Long, H. W.

doi:10.64898/2026.09.21.753036

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bioRxiv · 10.64898/2026.09.21.753036

A tumor-cell MHC-II program is associated with checkpoint-blockade outcomes across stages of bladder cancer

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Abstract

Purpose: A minority of patients with bladder cancer derive lasting benefit from immunotherapy, and current biomarkers capture only part of the biology. We evaluated whether tumor-cell MHC class II defines an immune state associated with outcome across disease stages and after PD-1/PD-L1 blockade. Experimental Design: We localized differential MHC-II activity to malignant epithelial cells by single-nucleus and single-cell RNA sequencing and confirmed HLA-DR expression by immunohistochemistry in 122 specimens. Chromatin profiling and IFN-{gamma} stimulation of cell lines and primary tumors supported derivation of an 11-gene tumor-cell program. Associations were tested in 434 patients with non-muscle-invasive disease, 82 receiving neoadjuvant pembrolizumab, and 288 receiving atezolizumab for metastatic disease. Results: Tumor-cell MHC-II was present in approximately one third of bladder cancers, and malignant cells accounted for the differential signal between MHC-II-high and MHC-II-low tumors. The program was inducible by IFN-{gamma} through JAK/STAT signaling. Within luminal non-muscle-invasive disease, MHC-II-low status was associated with progression (HR 3.31, 95% CI 1.37 to 7.99). In PURE-01, the 11-gene program was associated with pathological complete response (52% versus 24%, p = 0.018) and recurrence-free survival (p = 0.0054), retaining an independent association in models including tumor mutational burden and PD-L1. In bladder-primary metastatic disease, program-high status was associated with overall survival in unadjusted analysis (HR 0.62, 95% CI 0.44 to 0.89); the association did not extend to upper tract tumors (interaction p = 0.0018). Conclusions: Tumor-cell MHC-II defines an inducible state associated with outcomes across bladder cancer stages and after checkpoint blockade, supporting prospective evaluation by RNA and immunohistochemistry.

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Bellmunt, J., Xie, Y., Gomez Munoz, M., Kukreja, S., Walker, S., He, R., Li, R., Qiu, X., Zhang, T., Rodriguez, P., Garcia Gonzalez, D., Epstein, I., Parera, J., Juanpere, N., Lorenzo, M., Buisan, O., Senserrich, J., Servian, P., Silva, T., Brown, M., Cabrera, C., Cejas, P., Long, H. W.. 2026-09-22. A tumor-cell MHC-II program is associated with checkpoint-blockade outcomes across stages of bladder cancer. https://doi.org/10.64898/2026.09.21.753036

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