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

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

  • Cancer Lett. 2024 Jan 24:216642. doi: 10.1016/j.canlet.2024.216642.
Chenying Liu 1,  Xiaolong Qian 1,  Chunyan Yu 2,  Xiaoqing Xia 1,  Jiazhen Li 1,  Yaqing Li 1,  Yongjie Xie 3,  Guangshen Gao 1,  Yuanming Song 1,  Meiyan Zhang 1,  Huiqin Xue 1,  Xiaozi Wang 1,  Hui Sun 1,  Jing Liu 4,  Weimin Deng 2,  Xiaojing Guo 5
Affiliations

Affiliations

  • 1 Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
  • 2 Tianjin Institute of Immunology, Department of Immunology, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Diseases and Microenvironment of Ministry of Education of China, Tianjin Medical University, Tianjin, 300070, China.
  • 3 Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
  • 4 Department of Breast Oncoplastic Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China.
  • 5 Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China. Electronic address: guoxiaojing@tjmuch.com.
PMID: 38278470 DOI: 10.1016/j.canlet.2024.216642
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.

Keywords

Ataxia-telangiectasia mutated (ATM); Immune checkpoint blockade; JNK/c-Jun signaling pathway; Triple-negative breast cancer (TNBC); Tumor necrosis factor-alpha (TNF-α).

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