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.

中文翻译：

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碱基切除修复可调节癌细胞中PD-L1的表达。

程序性死亡配体1（PD-L1）是影响癌症免疫治疗的关键因素；然而，PD-L1在癌细胞中的表达调控仍不清楚，特别是在DNA损伤，修复及其信号传导方面。在这里，我们证明了由外源施加的过氧化氢（H2O2）诱导的氧化DNA损伤上调了癌细胞中PD-L1的表达。此外，碱基切除修复（BER）酶DNA糖基化酶的耗竭会增强PD-L1对H2O2的上调。BER耗尽的细胞中PD-L1上调需要ATR / Chk1激酶活性，表明PD-L1上调是由DNA损伤信号介导的。对癌症基因组图谱的进一步分析显示，PD-L1的表达与BER /单链断裂修复（SSBR）的表达呈负相关，而BER / SSBR基因表达低的肿瘤则表现出较高的微卫星不稳定性和新抗原产生。因此，这些结果表明PD-L1表达在氧化应激下通过DNA损伤信号传导和新抗原-干扰素-γ途径被调节。