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  4. SMARCA4 regulates the NK-mediated killing of senescent cells
 
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SMARCA4 regulates the NK-mediated killing of senescent cells
File(s)
sciadv.adn2811.pdf (23.18 MB)
Published version
Author(s)
Reen, Virinder
D'Ambrosio, Mariantonietta
Søgaard, Pia Pernille
Tyson, Katie
Leeke, Bryony J
more
Type
Journal Article
Abstract
Induction of senescence by chemotherapeutic agents arrests cancer cells and activates immune surveillance responses to contribute to therapy outcomes. In this investigation, we searched for ways to enhance the NK-mediated elimination of senescent cells. We used a staggered screen approach, first identifying siRNAs potentiating the secretion of immunomodulatory cytokines to later test for their ability to enhance NK-mediated killing of senescent cells. We identified that genetic or pharmacological inhibition of SMARCA4 enhanced senescent cell elimination by NK cells. SMARCA4 expression is elevated during senescence and its inhibition derepresses repetitive elements, inducing the SASP via activation of cGAS/STING and MAVS/MDA5 pathways. Moreover, a PROTAC targeting SMARCA4 synergized with cisplatin to increase the infiltration of CD8 T cells and mature, activated NK cells in an immunocompetent model of ovarian cancer. Our results indicate that SMARCA4 inhibitors enhance NK-mediated surveillance of senescent cells and may represent senotherapeutic interventions for ovarian cancer.
Date Issued
2025-01
Date Acceptance
2024-12-11
Citation
Science Advances, 2025, 11 (3)
URI
http://hdl.handle.net/10044/1/116011
URL
https://www.science.org/doi/10.1126/sciadv.adn2811
DOI
https://www.dx.doi.org/10.1126/sciadv.adn2811
ISSN
2375-2548
Publisher
American Association for the Advancement of Science
Journal / Book Title
Science Advances
Volume
11
Issue
3
Copyright Statement
Copyright © 2025 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).
License URL
https://creativecommons.org/licenses/by/4.0/
Identifier
https://www.science.org/doi/10.1126/sciadv.adn2811
Publication Status
Published
Article Number
eadn2811
Date Publish Online
2025-01-15
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