 The ATR inhibitor ceralasertib potentiates cancer checkpoint immunotherapy by regulating the tumor microenvironmentElizabeth L. Hardaker,
Emilio Sanseviero,
Ankur Karmokar,
Devon Taylor,
Marta Milo,
Chrysis Michaloglou,
Adina Hughes,
Mimi Mai,
Matthew King,
Anisha Solanki,
Lukasz Magiera,
Ricardo Miragaia,
Gozde Kar,
Nathan Standifer,
Michael Surace,
Shaan Gill,
Alison Peter,
Sara Talbot,
Sehmus Tohumeken,
Henderson Fryer,
Ali Mostafa,
Kathy Mulgrew,
Carolyn Lam,
Scott Hoffmann,
Daniel Sutton,
Larissa Carnevalli,
Fernando J. Calero-Nieto,
Gemma N. Jones,
Andrew J. Pierce,
Zena Wilson,
David Campbell,
Lynet Nyoni,
Carla P. Martins,
Tamara Baker,
Gilberto Serrano de Almeida,
Zainab Ramlaoui,
Abdel Bidar,
Benjamin Phillips,
Joseph Boland,
Sonia Iyer,
J. Carl Barrett,
Arsene-Bienvenu Loembé,
Serge Y. Fuchs,
Umamaheswar Duvvuri,
Pei-Jen Lou,
Melonie A. Nance,
Carlos Alberto Gomez Roca,
Elaine Cadogan,
Susan E. Critichlow,
Steven Fawell,
Mark Cobbold,
Emma Dean,
Viia Valge-Archer,
Alan Lau,
Dmitry I. Gabrilovich () and
Simon T. Barry ()
Nature Communications, 2024, vol. 15, issue 1, 1-20 Abstract: Abstract The 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. Date: 2024 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45996-4 Ordering information: This journal article can be ordered from DOI: 10.1038/s41467-024-45996-4 Access Statistics for this article Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie More articles in Nature Communications from Nature |
Is your work missing from RePEc? Here is how to contribute.
Questions or problems? Check the EconPapers FAQ or send mail to .
EconPapers is hosted by the
School of Business at Örebro University.