TY - JOUR
T1 - Expression of non-homologous end joining factor, Ku80, is negatively correlated with PD-L1 expression in cancer cells after X-ray irradiation
AU - Kumazawa, Takuya
AU - Mori, Yasumasa
AU - Sato, Hiro
AU - Permata, Tiara Bunga Mayang
AU - Uchihara, Yuki
AU - Noda, Shin Ei
AU - Okada, Kohei
AU - Kakoti, Sangeeta
AU - Suzuki, Keiji
AU - Ikota, Hayato
AU - Yokoo, Hideaki
AU - Gondhowiardjo, Soehartati
AU - Nakano, Takashi
AU - Ohno, Tatsuya
AU - Shibata, Atsushi
N1 - Funding Information:
This study was supported by JSPS KAKENHI (grant nos. JP 17H04713 and JP19K08195), the Takeda Science Foundation, the Uehara Memorial Foundation, the Astellas Foundation for Research on Metabolic Disorders, The Kanae Foundation for the Promotion of Medical Science, the Yasuda Memorial Medicine Foundation and the Nakajima Foundation. This study was also supported by the Program of the Network‑Type Joint Usage/Research Centre for Radiation Disaster Medical Science of Hiroshima University, Nagasaki University and Fukushima Medical University and the Grants‑in‑Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan for programmes for Leading Graduate Schools, Cultivating Global Leaders in Heavy Ion Therapeutics and Engineering.
Publisher Copyright:
© 2022 Spandidos Publications. All rights reserved.
PY - 2022/1
Y1 - 2022/1
N2 - The growing importance of antitumour immunity by cancer immunotherapy has prompted studies on radiotherapy-induced immune response. Previous studies have indicated that programmed cell death-1 ligand (PD-L1) expression is regulated by DNA damage signalling. However, PD-L1 up-regulation after radiotherapy has not been fully investigated at the clinical level, particularly in the context of expression of DNA repair factors. The present study exam- ined the correlation of mRNA expression between PD-L1 and non-homologous end joining (NHEJ) factors using The Cancer Genome Atlas database analysis. Among NHEJ factors, Ku80 mRNA expression was negatively correlated with PD-L1 mRNA expression levels in several types of cancer (colon adenocarcinoma, breast invasive carcinoma, skin cutaneous melanoma, lung adenocarcinoma, head and neck squamous cell carcinoma, uterine corpus endometrial carci- noma, cervical squamous cell carcinoma and endocervical adenocarcinoma). To verify the negative correlation in clinical samples, the present study analysed whether Ku80 expression levels affected PD-L1 up-regulation after radiotherapy using cervical squamous cell carcinoma samples. Quantitative evaluation using software analysis of immunohistochemi- cally stained slides revealed that patients with low Ku80 positivity in biopsy specimens demonstrated increased PD-L1 expression levels after 10 Gy irradiation (Spearman's rank correlation coefficient=-0.274; P=0.017). Furthermore, PD-L1 induction levels in tumour cells after 10 Gy of irradiation were significantly inversely correlated with Ku80 expression levels (Spearman's rank correlation coefficient=-0.379; P<0.001). The present study also confirmed that short interfering RNA-mediated Ku80 depletion was associated with greater X-ray-induced PD-L1 up-regulation in HeLa cells. These results indicated that radiotherapy could enhance PD-L1 induction in tumour cells with low Ku80 expression in a clinical setting. Furthermore, these data highlighted Ku80 as a potential predictive biomarker for immune checkpoint therapy combined with radiotherapy.
AB - The growing importance of antitumour immunity by cancer immunotherapy has prompted studies on radiotherapy-induced immune response. Previous studies have indicated that programmed cell death-1 ligand (PD-L1) expression is regulated by DNA damage signalling. However, PD-L1 up-regulation after radiotherapy has not been fully investigated at the clinical level, particularly in the context of expression of DNA repair factors. The present study exam- ined the correlation of mRNA expression between PD-L1 and non-homologous end joining (NHEJ) factors using The Cancer Genome Atlas database analysis. Among NHEJ factors, Ku80 mRNA expression was negatively correlated with PD-L1 mRNA expression levels in several types of cancer (colon adenocarcinoma, breast invasive carcinoma, skin cutaneous melanoma, lung adenocarcinoma, head and neck squamous cell carcinoma, uterine corpus endometrial carci- noma, cervical squamous cell carcinoma and endocervical adenocarcinoma). To verify the negative correlation in clinical samples, the present study analysed whether Ku80 expression levels affected PD-L1 up-regulation after radiotherapy using cervical squamous cell carcinoma samples. Quantitative evaluation using software analysis of immunohistochemi- cally stained slides revealed that patients with low Ku80 positivity in biopsy specimens demonstrated increased PD-L1 expression levels after 10 Gy irradiation (Spearman's rank correlation coefficient=-0.274; P=0.017). Furthermore, PD-L1 induction levels in tumour cells after 10 Gy of irradiation were significantly inversely correlated with Ku80 expression levels (Spearman's rank correlation coefficient=-0.379; P<0.001). The present study also confirmed that short interfering RNA-mediated Ku80 depletion was associated with greater X-ray-induced PD-L1 up-regulation in HeLa cells. These results indicated that radiotherapy could enhance PD-L1 induction in tumour cells with low Ku80 expression in a clinical setting. Furthermore, these data highlighted Ku80 as a potential predictive biomarker for immune checkpoint therapy combined with radiotherapy.
KW - Biomarker
KW - DNA damage response
KW - Immunotherapy
KW - Ku80
KW - Programmed death-1 ligand
KW - Radiotherapy
UR - http://www.scopus.com/inward/record.url?scp=85120788842&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85120788842&partnerID=8YFLogxK
U2 - 10.3892/OL.2021.13147
DO - 10.3892/OL.2021.13147
M3 - Article
AN - SCOPUS:85120788842
SN - 1792-1074
VL - 23
JO - Oncology Letters
JF - Oncology Letters
IS - 1
M1 - 29
ER -
