Abstract

Accumulating evidence suggests that exogenous cellular stress induces PD-L1 upregulation in cancer. A DNA double-strand break (DSB) is the most critical type of genotoxic stress, but the involvement of DSB repair in PD-L1 expression has not been investigated. Here we show that PD-L1 expression in cancer cells is upregulated in response to DSBs. This upregulation requires ATM/ATR/Chk1 kinases. Using an siRNA library targeting DSB repair genes, we discover that BRCA2 depletion enhances Chk1-dependent PD-L1 upregulation after X-rays or PARP inhibition. In addition, we show that Ku70/80 depletion substantially enhances PD-L1 upregulation after X-rays. The upregulation by Ku80 depletion requires Chk1 activation following DNA end-resection by Exonuclease 1. DSBs activate STAT1 and STAT3 signalling, and IRF1 is required for DSB-dependent PD-L1 upregulation. Thus, our findings reveal the involvement of DSB repair in PD-L1 expression and provide mechanistic insight into how PD-L1 expression is regulated after DSBs.

Details

Title
DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells
Author
Sato, Hiro 1 ; Niimi, Atsuko 2 ; Yasuhara, Takaaki 3   VIAFID ORCID Logo  ; Tiara Bunga Mayang Permata 1 ; Hagiwara, Yoshihiko 1 ; Isono, Mayu 4 ; Nuryadi, Endang 1 ; Sekine, Ryota 4 ; Oike, Takahiro 1 ; Kakoti, Sangeeta 1 ; Yoshimoto, Yuya 1 ; Held, Kathryn D 5 ; Suzuki, Yoshiyuki 6 ; Kono, Koji 7 ; Miyagawa, Kiyoshi 3 ; Nakano, Takashi 8 ; Shibata, Atsushi 9 

1  Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan 
2  Research Program for Heavy Ion Therapy, Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research (GIAR), Maebashi, Gunma, Japan 
3  Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan 
4  Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma, Japan 
5  Department of Radiation Oncology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA; International Open Laboratory, Gunma University Initiative for Advanced Research (GIAR), Maebashi, Gunma, Japan 
6  Department of Radiation Oncology, Fukushima Medical University, Fukushima, Japan 
7  Department of Gastrointestinal Tract Surgery, Fukushima Medical University, Fukushima, Japan 
8  Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan; Research Program for Heavy Ion Therapy, Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research (GIAR), Maebashi, Gunma, Japan 
9  Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma, Japan; Education and Research Support Center, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan 
Pages
1-11
Publication year
2017
Publication date
Nov 2017
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-017-01883-9
ProQuest document ID
1967846707
Copyright
© 2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.