The ATR inhibitor ceralasertib potentiates cancer checkpoint immunotherapy by regulating the tumor microenvironment
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Published:2024-02-24
Issue:1
Volume:15
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Hardaker Elizabeth L., Sanseviero Emilio, Karmokar Ankur, Taylor Devon, Milo Marta, Michaloglou Chrysis, Hughes AdinaORCID, Mai Mimi, King Matthew, Solanki Anisha, Magiera Lukasz, Miragaia Ricardo, Kar Gozde, Standifer NathanORCID, Surace Michael, Gill Shaan, Peter Alison, Talbot Sara, Tohumeken Sehmus, Fryer Henderson, Mostafa Ali, Mulgrew Kathy, Lam Carolyn, Hoffmann ScottORCID, Sutton Daniel, Carnevalli LarissaORCID, Calero-Nieto Fernando J.ORCID, Jones Gemma N., Pierce Andrew J.ORCID, Wilson Zena, Campbell David, Nyoni LynetORCID, Martins Carla P., Baker Tamara, Serrano de Almeida Gilberto, Ramlaoui ZainabORCID, Bidar Abdel, Phillips Benjamin, Boland Joseph, Iyer SoniaORCID, Barrett J. Carl, Loembé Arsene-Bienvenu, Fuchs Serge Y.ORCID, Duvvuri Umamaheswar, Lou Pei-JenORCID, Nance Melonie A., Gomez Roca Carlos AlbertoORCID, Cadogan ElaineORCID, Critichlow Susan E., Fawell Steven, Cobbold Mark, Dean EmmaORCID, Valge-Archer Viia, Lau AlanORCID, Gabrilovich Dmitry I.ORCID, Barry Simon T.ORCID
Abstract
AbstractThe Ataxia telangiectasia and Rad3-related (ATR) inhibitor ceralasertib in combination with the PD-L1 antibody durvalumab demonstrated encouraging clinical benefit in melanoma and lung cancer patients who progressed on immunotherapy. Here we show that modelling of intermittent ceralasertib treatment in mouse tumor models reveals CD8+ T-cell dependent antitumor activity, which is separate from the effects on tumor cells. Ceralasertib suppresses proliferating CD8+ T-cells on treatment which is rapidly reversed off-treatment. Ceralasertib causes up-regulation of type I interferon (IFNI) pathway in cancer patients and in tumor-bearing mice. IFNI is experimentally found to be a major mediator of antitumor activity of ceralasertib in combination with PD-L1 antibody. Improvement of T-cell function after ceralasertib treatment is linked to changes in myeloid cells in the tumor microenvironment. IFNI also promotes anti-proliferative effects of ceralasertib on tumor cells. Here, we report that broad immunomodulatory changes following intermittent ATR inhibition underpins the clinical therapeutic benefit and indicates its wider impact on antitumor immunity.
Publisher
Springer Science and Business Media LLC
Reference44 articles.
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