Base excision repair regulates PD-L1 expression in cancer cells

Tiara Bunga Mayang Permata, Yoshihiko Hagiwara, Hiro Sato, Takaaki Yasuhara, Takahiro Oike, Soehartati Argadikoesoema, Kathryn D. Held, Takashi Nakano, Atsushi Shibata

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13 Citations (Scopus)

Abstract

Programmed death-ligand 1 (PD-L1) is a key factor influencing cancer immunotherapy; however, the regulation of PD-L1 expression in cancer cells remains unclear, particularly regarding DNA damage, repair and its signalling. Herein, we demonstrate that oxidative DNA damage induced by exogenously applied hydrogen peroxide (H 2 O 2 ) upregulates PD-L1 expression in cancer cells. Further, depletion of the base excision repair (BER) enzyme DNA glycosylase augments PD-L1 upregulation in response to H 2 O 2 . PD-L1 upregulation in BER-depleted cells requires ATR/Chk1 kinase activities, demonstrating that PD-L1 upregulation is mediated by DNA damage signalling. Further analysis of The Cancer Genome Atlas revealed that the expression of PD-L1 is negatively correlated with that of the BER/single-strand break repair (SSBR) and tumours with low BER/SSBR gene expression show high microsatellite instability and neoantigen production. Hence, these results suggest that PD-L1 expression is regulated in cancer cells via the DNA damage signalling and neoantigen–interferon-γ pathway under oxidative stress.

Original languageEnglish
JournalOncogene
DOIs
Publication statusPublished - 1 Jan 2019

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    Permata, T. B. M., Hagiwara, Y., Sato, H., Yasuhara, T., Oike, T., Argadikoesoema, S., Held, K. D., Nakano, T., & Shibata, A. (2019). Base excision repair regulates PD-L1 expression in cancer cells. Oncogene. https://doi.org/10.1038/s41388-019-0733-6