Base excision repair regulates PD-L1 expression in cancer cells

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.

Highlights

  • Exogenous oxidative DNA damage upregulates PD-L1 expression in cancer cells.

  • BER deficiency augments PD-L1 upregulation following oxidative DNA damage.

  • Tumour samples with BER/SSBR mutations show high microsatellite instability, neoantigen and PD-L1 expression.

  • PD-L1 and BER/SSBR gene expressions are negatively correlated in clinical specimens.

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Data availability

All relevant data are available from the corresponding author(s) upon reasonable request.

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Acknowledgements

We thank Yoshimi Omi, Akiko Shibata, Yoko Hayashi, Shiho Nakanishi, Yukihiko Yoshimatsu and Yuka Hirota for assisting with the lab work.

Funding

This work was supported by the Program of the network-type Joint Usage/Research Center for Radiation Disaster Medical Science of Hiroshima University, Nagasaki University and Fukushima Medical University. This work was also supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan for programs for Leading Graduate Schools, Cultivating Global Leaders in Heavy Ion Therapeutics and Engineering.

Author contributions

A.S. designed the experiments and wrote the paper with T.B.M.P. The experiments including immunoblotting, qPCR and flow cytometry were performed by T.B.M.P., H.S., Y.H. and A.S. The dataset of TCGA was developed by T.Y. The TCGA analysis was performed by T.B.M.P. and Y.H. under the supervision of T.Y. Acquired data was analysed and interpreted by T.B.M.P., H.S., T.Y. and A.S. The manuscript was reviewed by T.O., K.D.H. and T.N. Administrative, technical or material support was provided by T.O., S. G. and T.N. The study was supervised by A.S.

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Correspondence to Atsushi Shibata.

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Permata, T.B.M., Hagiwara, Y., Sato, H. et al. Base excision repair regulates PD-L1 expression in cancer cells. Oncogene 38, 4452–4466 (2019). https://doi.org/10.1038/s41388-019-0733-6

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