A tumor-cell MHC-II program is associated with checkpoint-blockade outcomes across stages of bladder cancer
- 1Dana-Farber Cancer Institute
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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BibTeX
@misc{bellmunt2026tumorcell,
title = {{A tumor-cell MHC-II program is associated with checkpoint-blockade outcomes across stages of bladder cancer}},
author = {J. Bellmunt and Y. Xie and M. Gomez Munoz and S. Kukreja and S. Walker and R. He and R. Li and X. Qiu and T. Zhang and P. Rodriguez and D. Garcia Gonzalez and I. Epstein and J. Parera and N. Juanpere and M. Lorenzo and O. Buisan and J. Senserrich and P. Servian and T. Silva and M. Brown and C. Cabrera and P. Cejas and H. W. Long},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.21.753036},
url = {https://www.biorxiv.org/content/10.64898/2026.09.21.753036v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - A tumor-cell MHC-II program is associated with checkpoint-blockade outcomes across stages of bladder cancer
AU - J. Bellmunt
AU - Y. Xie
AU - M. Gomez Munoz
AU - S. Kukreja
AU - S. Walker
AU - R. He
AU - R. Li
AU - X. Qiu
AU - T. Zhang
AU - P. Rodriguez
AU - D. Garcia Gonzalez
AU - I. Epstein
AU - J. Parera
AU - N. Juanpere
AU - M. Lorenzo
AU - O. Buisan
AU - J. Senserrich
AU - P. Servian
AU - T. Silva
AU - M. Brown
AU - C. Cabrera
AU - P. Cejas
AU - H. W. Long
PY - 2026
DA - 2026/09/21
PB - bioRxiv
DO - 10.64898/2026.09.21.753036
UR - https://www.biorxiv.org/content/10.64898/2026.09.21.753036v1
AB - 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.
ER -