Università Vita-Salute San Raffaele - Department of Urology; Università Vita-Salute San Raffaele; Vita-Salute San Raffaele University, San Raffaele Hospital, Urological Research Institute
Northwestern University, Feinberg School of Medicine - Departments of Urology, and Biochemistry and Molecular Genetics; Northwestern University - Department of Urology
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.
Robertson, A. Gordon and Meghani, Khyati and Cooley, Lauren Folgosa and McLaughlin, Kimberly A. and Fall, Leigh Ann and Yu, Yanni and Castro, Mauro A. A. and Groeneveld, Clarice S. and De Reynies, Aurélien and Nazarov, Vadim I. and Tsvetkov, Vasily O. and Choy, Bonnie and Raggi, Daniele and Marandino, Laura and Montorsi, Francesco and Montorsi, Francesco and Powles, Thomas and Necchi, Andrea and Meeks, Joshua and Meeks, Joshua, Expression-Based Subtypes Define Pathologic Response to Neoadjuvant Immune-Checkpoint Inhibitors in Muscle-Invasive Bladder Cancer. Available at SSRN: https://ssrn.com/abstract=3924600 or http://dx.doi.org/10.2139/ssrn.3924600
This version of the paper has not been formally peer reviewed.
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