作者
Elizabeth 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, Simon T Barry
发表日期
2024/2/24
期刊
Nature Communications
卷号
15
期号
1
页码范围
1700
出版商
Nature Publishing Group UK
简介
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 …
学术搜索中的文章
EL Hardaker, E Sanseviero, A Karmokar, D Taylor… - Nature Communications, 2024