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

Hiro Sato, Atsuko Niimi, Takaaki Yasuhara, Tiara Bunga Mayang Permata, Yoshihiko Hagiwara, Mayu Isono, Endang Nuryadi, Ryota Sekine, Takahiro Oike, Sangeeta Kakoti, Yuya Yoshimoto, Kathryn D. Held, Yoshiyuki Suzuki, Koji Kono, Kiyoshi Miyagawa, Takashi Nakano and Atsushi Shibata ()
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Hiro Sato: Gunma University Graduate School of Medicine
Atsuko Niimi: Gunma University Initiative for Advanced Research (GIAR)
Takaaki Yasuhara: The University of Tokyo
Tiara Bunga Mayang Permata: Gunma University Graduate School of Medicine
Yoshihiko Hagiwara: Gunma University Graduate School of Medicine
Mayu Isono: Gunma University
Endang Nuryadi: Gunma University Graduate School of Medicine
Ryota Sekine: Gunma University
Takahiro Oike: Gunma University Graduate School of Medicine
Sangeeta Kakoti: Gunma University Graduate School of Medicine
Yuya Yoshimoto: Gunma University Graduate School of Medicine
Kathryn D. Held: Massachusetts General Hospital/Harvard Medical School
Yoshiyuki Suzuki: Fukushima Medical University
Koji Kono: Fukushima Medical University
Kiyoshi Miyagawa: The University of Tokyo
Takashi Nakano: Gunma University Graduate School of Medicine
Atsushi Shibata: Gunma University

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01883-9

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