Base excision repair regulates PD-L1 expression in cancer cells

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. 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.