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

Author

Listed:
  • 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
    Gunma University Initiative for Advanced Research (GIAR))

  • Yoshiyuki Suzuki

    (Fukushima Medical University)

  • Koji Kono

    (Fukushima Medical University)

  • Kiyoshi Miyagawa

    (The University of Tokyo)

  • Takashi Nakano

    (Gunma University Graduate School of Medicine
    Gunma University Initiative for Advanced Research (GIAR))

  • Atsushi Shibata

    (Gunma University
    Graduate School of Medicine, Gunma University)

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.

Suggested Citation

  • 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 , 2017. "DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01883-9
    DOI: 10.1038/s41467-017-01883-9
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    Cited by:

    1. I.-M. Launonen & N. Lyytikäinen & J. Casado & E. A. Anttila & A. Szabó & U.-M. Haltia & C. A. Jacobson & J. R. Lin & Z. Maliga & B. E. Howitt & K. C. Strickland & S. Santagata & K. Elias & A. D. D’And, 2022. "Single-cell tumor-immune microenvironment of BRCA1/2 mutated high-grade serous ovarian cancer," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Elizabeth L. Hardaker & Emilio Sanseviero & Ankur Karmokar & Devon Taylor & Marta Milo & Chrysis Michaloglou & Adina Hughes & Mimi Mai & Matthew King & Anisha Solanki & Lukasz Magiera & Ricardo Miraga, 2024. "The ATR inhibitor ceralasertib potentiates cancer checkpoint immunotherapy by regulating the tumor microenvironment," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    3. Zhen Shu & Bhakti Dwivedi & Jeffrey M. Switchenko & David S. Yu & Xingming Deng, 2024. "PD-L1 deglycosylation promotes its nuclear translocation and accelerates DNA double-strand-break repair in cancer," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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