Expression of non-homologous end joining factor, Ku80, is negatively correlated with PD-L1 expression in cancer cells after X-ray irradiation

Takuya Kumazawa, Yasumasa Mori, Hiro Sato, Tiara Bunga Mayang Permata, Yuki Uchihara, Shin Ei Noda, Kohei Okada, Sangeeta Kakoti, Keiji Suzuki, Hayato Ikota, Hideaki Yokoo, Soehartati Gondhowiardjo, Takashi Nakano, Tatsuya Ohno, Atsushi Shibata

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number29
JournalOncology Letters
Volume23
Issue number1
DOIs
Publication statusPublished - Jan 2022

Keywords

  • Biomarker
  • DNA damage response
  • Immunotherapy
  • Ku80
  • Programmed death-1 ligand
  • Radiotherapy

Fingerprint

Dive into the research topics of 'Expression of non-homologous end joining factor, Ku80, is negatively correlated with PD-L1 expression in cancer cells after X-ray irradiation'. Together they form a unique fingerprint.

Cite this