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Oncogene. 2019 Jun;38(23):4452-4466. doi: 10.1038/s41388-019-0733-6. Epub 2019 Feb 12.

Base excision repair regulates PD-L1 expression in cancer cells.

Author information

1
Department of Radiation Oncology, Graduate School of Medicine, Gunma University, Maebashi, Gunma, 371-8511, Japan.
2
Department of Radiotherapy, Dr. Cipto Mangunkusumo National General Hospital, Jakarta, Indonesia.
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
Department of Radiation Oncology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, 02114, USA.
5
International Open Laboratory, Gunma University Initiative for Advanced Research (GIAR), Maebashi, Gunma, 371-8511, Japan.
6
Education and Research Support Center, Graduate School of Medicine, Gunma University, Maebashi, Gunma, 371-8511, Japan. shibata.at@gunma-u.ac.jp.

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 (H2O2) 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 H2O2. 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.

PMID:
30755733
DOI:
10.1038/s41388-019-0733-6

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