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 identify five distinctive genetic and transcriptomic programs and validate these in an independent neoadjuvant CPI trial to identify the features of response or resistance to CPI. By modeling the regulatory network, we identify the histone demethylase KDM5B as a repressor of tumor immune signaling pathways in one resistant subtype (S1, Luminal-excluded) and demonstrate 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.
Nature communications. 2023 Apr 27*** epublish ***
A Gordon Robertson, Khyati Meghani, Lauren Folgosa Cooley, Kimberly A McLaughlin, Leigh Ann Fall, Yanni Yu, Mauro A A Castro, Clarice S Groeneveld, Aurélien de Reyniès, Vadim I Nazarov, Vasily O Tsvetkov, Bonnie Choy, Daniele Raggi, Laura Marandino, Francesco Montorsi, Thomas Powles, Andrea Necchi, Joshua J Meeks
Dxige Research Inc., Courtenay, BC, Canada., Departments of Urology, and Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA., Bioinformatics and Systems Biology Laboratory, Federal University of Paraná, Curitiba, Brazil., Université Paris Cité, Centre de Recherche sur l'Inflammation (CRI), INSERM, U1149, CNRS, ERL 8252, F-75018, Paris, France., Université Paris Cité, INSERM U1138 Centre de Recherches des Cordeliers, APHP, SeQOIA-IT, Paris, France., ImmunoMind Inc., Berkeley, CA, USA., Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA., Department of Medical Oncology, IRCCS San Raffaele Hospital and Scientific Institute, Milan, Italy., Department of Urology, IRCCS San Raffaele Hospital and Scientific Institute, Milan, Italy., Barts Experimental Cancer Medicine Centre, Barts Cancer Institute, Queen Mary University of London, London, UK., Departments of Urology, and Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA. .