Sato, HiroNiimi, AtsukoYasuhara, TakaakiPermata, Tiara Bunga MayangHagiwara, YoshihikoIsono, MayuNuryadi, EndangSekine, RyotaOike, TakahiroKakoti, SangeetaYoshimoto, YuyaHeld, KathrynSuzuki, YoshiyukiKono, KojiMiyagawa, KiyoshiNakano, TakashiShibata, Atsushi2017-12-062017Sato, H., A. Niimi, T. Yasuhara, T. B. M. Permata, Y. Hagiwara, M. Isono, E. Nuryadi, et al. 2017. “DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells.” Nature Communications 8 (1): 1751. doi:10.1038/s41467-017-01883-9. http://dx.doi.org/10.1038/s41467-017-01883-9.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34493034Accumulating 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.en-USJournal Article2017-12-0610.1038/s41467-017-01883-9