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

Author

Listed:
  • 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
    Oncologie Moleculaire, Institut Curie, Equipe Labellisée Ligue Contre le Cancer)

  • 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
    Vita-Salute San Raffaele University)

  • Thomas Powles

    (Queen Mary University of London)

  • Andrea Necchi

    (IRCCS San Raffaele Hospital and Scientific Institute
    Vita-Salute San Raffaele University)

  • Joshua J. Meeks

    (Northwestern University, Feinberg School of Medicine
    Jesse Brown VA Medical Center)

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.

Suggested Citation

  • 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 & V, 2023. "Expression-based subtypes define pathologic response to neoadjuvant immune-checkpoint inhibitors in muscle-invasive bladder cancer," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37568-9
    DOI: 10.1038/s41467-023-37568-9
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