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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.

Author information

Sato H1, Niimi A2, Yasuhara T3, Permata TBM1, Hagiwara Y1, Isono M4, Nuryadi E1, Sekine R4, Oike T1, Kakoti S1, Yoshimoto Y1, Held KD5,6, Suzuki Y7, Kono K8, Miyagawa K3, Nakano T1,2, Shibata A9,10.
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.