A tumor-cell MHC-II program is associated with checkpoint-blockade outcomes across stages of bladder cancer
Listed in
This article is not in any list yet, why not save it to one of your lists.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-γ 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-γ 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.
Translational Relevance
Bladder cancer is one of few malignancies in which immunotherapy is given from non-muscle-invasive through metastatic disease, yet tissue-based biomarkers identify only a subset of patients who derive benefit. We found approximately one third of bladder tumors express MHC class II on malignant epithelial cells. Within luminal non-muscle-invasive disease, MHC-II-low status marked a threefold higher progression risk. In checkpoint-treated muscle-invasive and bladder-primary metastatic disease, an 11-gene tumor-cell program was associated with response and survival; in the neoadjuvant cohort, it added information beyond tumor mutational burden and PD-L1. Complementary assays, amenable to clinical-laboratory implementation, capture different aspects of this state: bulk RNA was used in the outcome analyses, whereas HLA-DR immunohistochemistry demonstrated tumor-cell protein expression in a 122 specimen TMA. Because the program is inducible, a negative result may identify tumors lacking inflammatory input rather than tumors incapable of responding. As enfortumab vedotin plus pembrolizumab becomes standard of care, tsMHC-II is a candidate biomarker of the immunotherapy-sensitive component of such regimens and warrants prospective evaluation across the treatment course.
