The ATR inhibitor ceralasertib potentiates cancer checkpoint immunotherapy by regulating the tumor microenvironment

被引：11

作者：

Hardaker, Elizabeth L. ^{[1
]}

Sanseviero, Emilio ^{[2
]}

Karmokar, Ankur ^{[1
]}

Taylor, Devon ^{[2
]}

Milo, Marta ^{[1
]}

Michaloglou, Chrysis ^{[1
]}

Hughes, Adina ^{[1
]}

Mai, Mimi ^{[2
]}

King, Matthew ^{[1
]}

Solanki, Anisha ^{[1
]}

Magiera, Lukasz ^{[1
]}

Miragaia, Ricardo ^{[1
]}

Kar, Gozde ^{[1
]}

Standifer, Nathan ^{[2
,16
]}

Surace, Michael ^{[2
]}

Gill, Shaan ^{[1
]}

Peter, Alison ^{[1
]}

Talbot, Sara ^{[1
]}

Tohumeken, Sehmus ^{[2
]}

Fryer, Henderson ^{[2
]}

Mostafa, Ali ^{[2
]}

Mulgrew, Kathy ^{[2
]}

Lam, Carolyn ^{[1
]}

Hoffmann, Scott ^{[3
]}

Sutton, Daniel ^{[3
]}

Carnevalli, Larissa ^{[1
]}

Calero-Nieto, Fernando J. ^{[1
]}

Jones, Gemma N. ^{[1
]}

Pierce, Andrew J. ^{[1
,15
]}

Wilson, Zena ^{[1
]}

Campbell, David ^{[2
]}

Nyoni, Lynet ^{[1
]}

Martins, Carla P. ^{[1
]}

Baker, Tamara ^{[4
]}

de Almeida, Gilberto Serrano ^{[4
]}

Ramlaoui, Zainab ^{[2
]}

Bidar, Abdel ^{[5
]}

Phillips, Benjamin ^{[6
]}

Boland, Joseph ^{[2
]}

Iyer, Sonia ^{[7
]}

Barrett, J. Carl ^{[2
]}

Loembe, Arsene-Bienvenu ^{[8
]}

Fuchs, Serge Y. ^{[9
]}

Duvvuri, Umamaheswar ^{[10
,11
]}

Lou, Pei-Jen ^{[12
]}

Nance, Melonie A. ^{[13
]}

Gomez Roca, Carlos Alberto ^{[14
]}

Cadogan, Elaine ^{[1
]}

Critichlow, Susan E. ^{[1
]}

Fawell, Steven ^{[7
]}

机构：

[1] Oncol R&D, AstraZeneca, Cambridge, England

[2] Oncol R&D, AstraZeneca, Gaithersburg, MD 20878 USA

[3] Imaging & Data Analyt, AstraZeneca, Cambridge, England

[4] CPSS AST, AstraZeneca, Cambridge, England

[5] CPSS, Imaging, AstraZeneca, Gothenburg, Sweden

[6] AstraZeneca, R&D, Data Sci & Quantitat Biol, Discovery Sci, Cambridge, England

[7] AstraZeneca, Oncol R&D, Boston, MA USA

[8] Early Clin Dev, AstraZeneca, Oss, Netherlands

[9] Univ Penn, Sch Vet Med, Dept Biomed Sci, Philadelphia, PA 19104 USA

[10] UPMC Dept Otolaryngol, 200 Lothrop St Suite 500, Pittsburgh, PA 15213 USA

[11] UPMC Hillman Canc Ctr, 200 Lothrop St Suite 500, Pittsburgh, PA 15213 USA

[12] Natl Taiwan Univ Hosp, Chung Shan S Rd 7, 7,Chung Shan S Rd Zhongshan S Rd, Taipei, Taiwan

[13] VA Pittsburgh Healthcare Syst, Univ Dr C, Pittsburgh, PA 15240 USA

[14] Inst Claudius Regaud, Canc Comprehens Ctr, Dept Pathol, IUCT O, 1 Ave Irene Joliot Curie, F-31059 Toulouse 9, France

[15] Crescendo Biol Ltd, Cambridge, England

[16] Tempest Therapeut, Brisbane, CA USA

来源：

NATURE COMMUNICATIONS | 2024年 / 15卷 / 01期

关键词：

CELLS; UBIQUITINATION; NSCLC;

D O I：

10.1038/s41467-024-45996-4

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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. The ATR inhibitor ceralasertib has shown clinical activity in combination with immune-checkpoint inhibitors in several cancer types. Here the authors report the anti-tumor activity and the immunomodulatory changes, dependent on up-regulation of type I interferon pathway, following intermittent ATR inhibition in preclinical cancer models.

引用

页数：20

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