Expression-based subtypes define pathologic response to neoadjuvant immune-checkpoint inhibitors in muscle-invasive bladder cancer

A. Gordon Robertson, Khyati Meghani, Lauren Folgosa Cooley, Kimberly A. McLaughlin, Leigh Ann Fall, Yanni Yu, Mauro A. A. Castro, Clarice S. Groeneveld, Aurélien Reyniès, Vadim I. Nazarov, Vasily O. Tsvetkov, Bonnie Choy, Daniele Raggi, Laura Marandino, Francesco Montorsi, Thomas Powles, Andrea Necchi and Joshua J. Meeks ()
Additional contact information
A. Gordon Robertson: Dxige Research Inc.
Khyati Meghani: Northwestern University, Feinberg School of Medicine
Lauren Folgosa Cooley: Northwestern University, Feinberg School of Medicine
Kimberly A. McLaughlin: Northwestern University, Feinberg School of Medicine
Leigh Ann Fall: Northwestern University, Feinberg School of Medicine
Yanni Yu: Northwestern University, Feinberg School of Medicine
Mauro A. A. Castro: Federal University of Paraná
Clarice S. Groeneveld: Université Paris Cité, Centre de Recherche sur l’Inflammation (CRI), INSERM, U1149, CNRS, ERL 8252
Aurélien Reyniès: Université Paris Cité, INSERM U1138 Centre de Recherches des Cordeliers, APHP, SeQOIA-IT
Vadim I. Nazarov: ImmunoMind Inc.
Vasily O. Tsvetkov: ImmunoMind Inc.
Bonnie Choy: Northwestern University, Feinberg School of Medicine
Daniele Raggi: IRCCS San Raffaele Hospital and Scientific Institute
Laura Marandino: IRCCS San Raffaele Hospital and Scientific Institute
Francesco Montorsi: IRCCS San Raffaele Hospital and Scientific Institute
Thomas Powles: Queen Mary University of London
Andrea Necchi: IRCCS San Raffaele Hospital and Scientific Institute
Joshua J. Meeks: Northwestern University, Feinberg School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract 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.

Date: 2023
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37568-9

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DOI: 10.1038/s41467-023-37568-9

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