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 de Reyniès; Vadim I. Nazarov; Vasily O. Tsvetkov; Bonnie Choy; Daniele Raggi; Laura Marandino; Francesco Montorsi; Thomas Powles; Andrea Necchi; Joshua J. Meeks

doi:10.1038/s41467-023-37568-9

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 de Reyniès, Vadim I. Nazarov, Vasily O. Tsvetkov, Bonnie Choy, Daniele Raggi, Laura Marandino, Francesco Montorsi, Thomas Powles, Andrea Necchi, Joshua J. Meeks^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

37 Scopus citations

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.

Original language	English (US)
Article number	2126
Journal	Nature communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-37568-9
State	Published - Dec 2023

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-023-37568-9

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Robertson, A. G., Meghani, K., Cooley, L. F., McLaughlin, K. A., Fall, L. A., Yu, Y., Castro, M. A. A., Groeneveld, C. S., de Reyniès, A., Nazarov, V. I., Tsvetkov, V. O., Choy, B., Raggi, D., Marandino, L., Montorsi, F., Powles, T., Necchi, A., & Meeks, J. J. (2023). Expression-based subtypes define pathologic response to neoadjuvant immune-checkpoint inhibitors in muscle-invasive bladder cancer. Nature communications, 14(1), Article 2126. https://doi.org/10.1038/s41467-023-37568-9

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

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.",

author = "Robertson, {A. Gordon} and Khyati Meghani and Cooley, {Lauren Folgosa} and McLaughlin, {Kimberly A.} and Fall, {Leigh Ann} and Yanni Yu and Castro, {Mauro A.A.} and Groeneveld, {Clarice S.} and {de Reyni{\`e}s}, Aur{\'e}lien and Nazarov, {Vadim I.} and Tsvetkov, {Vasily O.} and Bonnie Choy and Daniele Raggi and Laura Marandino and Francesco Montorsi and Thomas Powles and Andrea Necchi and Meeks, {Joshua J.}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "10.1038/s41467-023-37568-9",

language = "English (US)",

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Robertson, AG, Meghani, K, Cooley, LF, McLaughlin, KA, Fall, LA, Yu, Y, Castro, MAA, Groeneveld, CS, de Reyniès, A, Nazarov, VI, Tsvetkov, VO, Choy, B, Raggi, D, Marandino, L, Montorsi, F, Powles, T, Necchi, A & Meeks, JJ 2023, 'Expression-based subtypes define pathologic response to neoadjuvant immune-checkpoint inhibitors in muscle-invasive bladder cancer', Nature communications, vol. 14, no. 1, 2126. https://doi.org/10.1038/s41467-023-37568-9

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T1 - Expression-based subtypes define pathologic response to neoadjuvant immune-checkpoint inhibitors in muscle-invasive bladder cancer

AU - Robertson, A. Gordon

AU - Meghani, Khyati

AU - Cooley, Lauren Folgosa

AU - McLaughlin, Kimberly A.

AU - Fall, Leigh Ann

AU - Yu, Yanni

AU - Castro, Mauro A.A.

AU - Groeneveld, Clarice S.

AU - de Reyniès, Aurélien

AU - Nazarov, Vadim I.

AU - Tsvetkov, Vasily O.

AU - Choy, Bonnie

AU - Raggi, Daniele

AU - Marandino, Laura

AU - Montorsi, Francesco

AU - Powles, Thomas

AU - Necchi, Andrea

AU - Meeks, Joshua J.

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

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JF - Nature communications

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ER -

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

Abstract

ASJC Scopus subject areas

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