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Inhibition of ATM promotes PD-L1 expression by activating JNK/c-Jun/TNF-α signaling axis in triple-negative breast cancer.

Authors :
Liu, Chenying
Qian, Xiaolong
Yu, Chunyan
Xia, Xiaoqing
Li, Jiazhen
Li, Yaqing
Xie, Yongjie
Gao, Guangshen
Song, Yuanming
Zhang, Meiyan
Xue, Huiqin
Wang, Xiaozi
Sun, Hui
Liu, Jing
Deng, Weimin
Guo, Xiaojing
Source :
Cancer Letters. Apr2024, Vol. 586, pN.PAG-N.PAG. 1p.
Publication Year :
2024

Abstract

Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancer. Anti -PD-1/PD-L1 treatment for advanced TNBC is still limited to PD-L1-positive patients. Ataxia telangiectasia mutated (ATM) is a switch molecule for homologous recombination and repair. In this study, we found a significant negative correlation between ATM and PD-L1 in 4 TNBC clinical specimens by single-cell RNA sequencing (scRNA-seq), which was confirmed by immunochemical staining in 86 TNBC specimens. We then established ATM knockdown TNBC stable cell lines to perform in vitro studies and animal experiments, proving the negative regulation of PD-L1 by ATM via suppression of tumor necrosis factor-alpha (TNF-α), which was confirmed by cytokine array analysis of TNBC cell line and analysis of clinical specimens. We further found that ATM inhibits TNF-α via inactivating JNK/c-Jun by scRNA-seq, Western blot and luciferase reporter assays. Finally, we identified a negative correlation between changes in phospho-ATMS1981 and PD-L1 levels in TNBC post- and pre-neoadjuvant therapy. This study reveals a novel mechanism by which ATM negatively regulates PD-L1 by downregulating JNK/c-Jun/TNF-α in TNBC, shedding light on the wide application of immune checkpoint blockade therapy for treating multi-line-resistant TNBC. • A negative correlation between PD-L1and ATM expression in TNBC. • ATM negatively regulated PD-L1 expression through TNF-α. • ATM inhibits TNF-α by inactivating JNK/c-Jun signaling pathway. • ATM as a potential biomarker for diagnosis and prediction of immunotherapy. • The combination of ATM inhibitors and immunotherapy may benefit more patients with TNBC. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
03043835
Volume :
586
Database :
Academic Search Index
Journal :
Cancer Letters
Publication Type :
Academic Journal
Accession number :
175936686
Full Text :
https://doi.org/10.1016/j.canlet.2024.216642