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

52 Pages Posted: 15 Sep 2021 Publication Status: Review Complete

See all articles by A. Gordon Robertson

A. Gordon Robertson

Dxige Research Inc.

Khyati Meghani

Northwestern University - Department of Urology

Lauren Folgosa Cooley

Northwestern University - Department of Urology

Kimberly A. McLaughlin

Northwestern University - Department of Urology

Leigh Ann Fall

Northwestern University - Department of Urology

Yanni Yu

Northwestern University - Department of Urology

Mauro A. A. Castro

Federal University of Parana (UFPR) - Bioinformatics and Systems Biology Laboratory

Clarice S. Groeneveld

French League Against Cancer - Tumor Identity Cards Program

Aurélien De Reynies

French League Against Cancer - Tumor Identity Cards Program

Vadim I. Nazarov

ImmunoMind Inc.

Vasily O. Tsvetkov

ImmunoMind Inc.

Bonnie Choy

Northwestern University - Department of Pathology

Daniele Raggi

Università Vita-Salute San Raffaele - Department of Medical Oncology

Laura Marandino

Oncology Institute of Southern Switzerland - Service of Medical Oncology

Francesco Montorsi

Università Vita-Salute San Raffaele - Department of Urology; Università Vita-Salute San Raffaele; Vita-Salute San Raffaele University, San Raffaele Hospital, Urological Research Institute

Thomas Powles

Queen Mary University of London - Centre for Experimental Cancer Medicine

Andrea Necchi

Università Vita-Salute San Raffaele - Department of Medical Oncology

Joshua Meeks

Northwestern University, Feinberg School of Medicine - Departments of Urology, and Biochemistry and Molecular Genetics; Northwestern University - Department of Urology

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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 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.

Keywords: muscle-invasive bladder cancer, checkpoint immunotherapy, single-sample classifier, Digital Spatial Profiling, Connectivity Map, immune cell deconvolution, BCR, RNA-Seq, scRNA-Seq

Suggested Citation

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.

A. Gordon Robertson

Dxige Research Inc. ( email )

Canada

Khyati Meghani

Northwestern University - Department of Urology ( email )

Chicago, IL
United States

Lauren Folgosa Cooley

Northwestern University - Department of Urology ( email )

Chicago, IL
United States

Kimberly A. McLaughlin

Northwestern University - Department of Urology ( email )

Chicago, IL
United States

Leigh Ann Fall

Northwestern University - Department of Urology ( email )

Chicago, IL
United States

Yanni Yu

Northwestern University - Department of Urology ( email )

Chicago, IL
United States

Mauro A. A. Castro

Federal University of Parana (UFPR) - Bioinformatics and Systems Biology Laboratory ( email )

Brazil

Clarice S. Groeneveld

French League Against Cancer - Tumor Identity Cards Program ( email )

France

Aurélien De Reynies

French League Against Cancer - Tumor Identity Cards Program ( email )

France

Vadim I. Nazarov

ImmunoMind Inc. ( email )

Berkeley, CA
United States

Vasily O. Tsvetkov

ImmunoMind Inc. ( email )

Berkeley, CA
United States

Bonnie Choy

Northwestern University - Department of Pathology ( email )

Chicago, IL
United States

Daniele Raggi

Università Vita-Salute San Raffaele - Department of Medical Oncology

Milan
Italy

Laura Marandino

Oncology Institute of Southern Switzerland - Service of Medical Oncology ( email )

Bellinzona
Switzerland

Francesco Montorsi

Università Vita-Salute San Raffaele - Department of Urology

Milan
Italy

Università Vita-Salute San Raffaele

Via Olgettina 58
Milan, 20132
Italy

Vita-Salute San Raffaele University, San Raffaele Hospital, Urological Research Institute

Italy

Thomas Powles

Queen Mary University of London - Centre for Experimental Cancer Medicine

London
United Kingdom

Andrea Necchi

Università Vita-Salute San Raffaele - Department of Medical Oncology

Milan
Italy

Joshua Meeks (Contact Author)

Northwestern University, Feinberg School of Medicine - Departments of Urology, and Biochemistry and Molecular Genetics ( email )

Chicago, IL 60611
United States

Northwestern University - Department of Urology ( email )

Chicago, IL
United States

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