TY - JOUR
T1 - Base excision repair regulates PD-L1 expression in cancer cells
AU - Permata, Tiara Bunga Mayang
AU - Hagiwara, Yoshihiko
AU - Sato, Hiro
AU - Yasuhara, Takaaki
AU - Oike, Takahiro
AU - Argadikoesoema, Soehartati
AU - Held, Kathryn D.
AU - Nakano, Takashi
AU - Shibata, Atsushi
N1 - Funding Information:
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.
Publisher Copyright:
© 2019, Springer Nature Limited.
PY - 2019/6/6
Y1 - 2019/6/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85061483680&partnerID=8YFLogxK
U2 - 10.1038/s41388-019-0733-6
DO - 10.1038/s41388-019-0733-6
M3 - Article
AN - SCOPUS:85061483680
SN - 0950-9232
VL - 38
SP - 4452
EP - 4466
JO - Oncogene
JF - Oncogene
IS - 23
ER -
