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Nat Commun. 2017 Nov 24;8(1):1751. doi: 10.1038/s41467-017-01883-9.

DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells.

Author information

1
Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Gunma, 371-8511, Japan.
2
Research Program for Heavy Ion Therapy, Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research (GIAR), Maebashi, Gunma, 371-8511, Japan.
3
Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8655, Japan.
4
Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma, 371-8511, Japan.
5
Department of Radiation Oncology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, 02114, USA.
6
International Open Laboratory, Gunma University Initiative for Advanced Research (GIAR), Maebashi, Gunma, 371-8511, Japan.
7
Department of Radiation Oncology, Fukushima Medical University, Fukushima, 960-1295, Japan.
8
Department of Gastrointestinal Tract Surgery, Fukushima Medical University, Fukushima, 960-1295, Japan.
9
Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma, 371-8511, Japan. shibata.at@gunma-u.ac.jp.
10
Education and Research Support Center, Graduate School of Medicine, Gunma University, Maebashi, Gunma, 371-8511, Japan. shibata.at@gunma-u.ac.jp.

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.

PMID:
29170499
PMCID:
PMC5701012
DOI:
10.1038/s41467-017-01883-9
[Indexed for MEDLINE]
Free PMC Article

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