Expression-Based Subtypes Define Pathologic Response to Neoadjuvant Immune-Checkpoint Inhibitors in Muscle-Invasive Bladder Cancer

Checkpoint immunotherapy (CPI) has increased survival for some patients with advanced stage bladder cancer (BCa). However, most patients do not respond. Here, we characterized the tumor and immune microenvironment in pre- and post-treatment tumors from the PURE01 neoadjuvant pembrolizumab immunotherapy trial, using a consolidative approach that combined transcriptional and genetic profiling with digital spatial profiling. We identified five distinctive genetic and transcriptomic programs associated with resistance and response to CPI and validated these in an independent neoadjuvant CPI trial. By modeling the regulatory network, we identified histone demethylase KDM5B as a repressor of tumor immune signaling pathways and demonstrated that inhibition of KDM5B enhances immunogenicity in FGFR3- mutated BCa cells. Our study identifies signatures associated with response to CPI that can be used to molecularly stratify patients and suggests therapeutic alternatives for subtypes with poor response to neoadjuvant immunotherapy.