Journal
ONCOGENE
Volume 38, Issue 23, Pages 4452-4466Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41388-019-0733-6
Keywords
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Funding
- Program of the network-type Joint Usage/Research Center for Radiation Disaster Medical Science of Hiroshima University
- Nagasaki University
- Fukushima Medical University
- Ministry of Education, Culture, Sports, Science and Technology of Japan
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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/Chkl 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-gamma pathway under oxidative stress.
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