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

By Hiro Sato, A. Niimi, Takaaki Yasuhara, T. Permata, Yoshihiko Hagiwara, Mayu Isono, E. Nuryadi, Ryota Sekine, T. Oike, Sangeeta Kakoti and 7 more. Nature Communications, 2017

615 citations recorded by the source corpus.

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. PD-L1 is upregulated in many cancers due to exogenous cellular stress. Here the authors show that PD-L1 is upregulated in response to DNA double strand breaks via STAT and IRF1 signalling.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/22705f81acf16c73fd305349b3046e264bc8494c

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In Molecular Biology

1. Julien Sage

In Oncology

1. M. Hung
2. J. Hsu
3. Chia‐Wei Li
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Citations in the corpus

• Regulatory mechanisms of PD-1/PD-L1 in cancers (2024, background): “In addition, some non-CNV changes in the PD-L1 gene, such as deletion of PD-L1 exons, SNP site mutation [185], DNA double strand break [186], and PD-L1 3’ UTR structural variation [187], are emerging as new genetic mechanisms regulating PD-L1 gene expression.”
• Targeting DNA damage response promotes anti-tumor immunity through STING-mediated T-cell activation in small cell lung cancer (2019, positive): “Furthermore, some recent reports have demonstrated PD-L1 upregulation by DNA damage (40).”
• Mechanisms controlling PD-L1 expression in cancer (2019, background): “Consistently, DNA double-strand breaks (DSB) activate STAT signaling through ataxiatelangiectasia mutated (ATM)/ATM- and Rad3-related (ATR)/checkpoint kinase 1 (Chk1) kinases, resulting in upregulation of PD-L1 expression (Sato et al., 2017; Sun et al., 2018b).”