Base excision repair regulates PD-L1 expression in cancer cells.
Tiara Bunga Mayang PermataYoshihiko HagiwaraHiro SatoTakaaki YasuharaTakahiro OikeSoehartati GondhowiardjoKathryn D HeldTakashi NakanoAtsushi ShibataPublished in: Oncogene (2019)
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.
Keyphrases
- dna damage
- oxidative stress
- dna repair
- hydrogen peroxide
- poor prognosis
- gene expression
- induced apoptosis
- cell proliferation
- signaling pathway
- single cell
- nitric oxide
- squamous cell carcinoma
- dna methylation
- papillary thyroid
- transcription factor
- immune response
- ischemia reperfusion injury
- dendritic cells
- genome wide
- young adults
- cell death
- protein kinase
- genetic diversity
- pi k akt