High linear energy transfer carbon-ion irradiation upregulates PD-L1 expression more significantly than X-rays in human osteosarcoma U2OS cells

• Published in: Journal of radiation research Vol. 62; no. 5; pp. 773 - 781
• Main Authors: Permata, Tiara Bunga Mayang, Sato, Hiro, Gu, Wenchao, Kakoti, Sangeeta, Uchihara, Yuki, Yoshimatsu, Yukihiko, Sato, Itaru, Kato, Reona, Yamauchi, Motohiro, Suzuki, Keiji, Oike, Takahiro, Tsushima, Yoshito, Gondhowiardjo, Soehartati, Ohno, Tatsuya, Yasuhara, Takaaki, Shibata, Atsushi
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.09.2021
• Subjects: Ataxia; Ataxia Telangiectasia Mutated Proteins - antagonists & inhibitors; Ataxia Telangiectasia Mutated Proteins - physiology; B7-H1 Antigen - biosynthesis; B7-H1 Antigen - genetics; Biological effects; Bone cancer; Bone Neoplasms - pathology; Cancer; Carbon; Cell Line, Tumor; Effectiveness; Energy transfer; Fundamental Radiation Science; Gene Expression Regulation, Neoplastic - radiation effects; Heavy Ion Radiotherapy; Humans; Image resolution; Imaging, Three-Dimensional; Immunofluorescence; Interferon Regulatory Factor-1 - biosynthesis; Interferon Regulatory Factor-1 - genetics; Ion irradiation; Ionizing radiation; Kinases; Linear Energy Transfer; Linear energy transfer (LET); Morpholines - pharmacology; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Osteosarcoma - pathology; Phosphorylation; Phosphorylation - radiation effects; Protein Processing, Post-Translational - radiation effects; Pyrazines - pharmacology; Pyrones - pharmacology; Relative biological effectiveness (RBE); RNA, Messenger - biosynthesis; RNA, Messenger - genetics; RNA, Neoplasm - biosynthesis; RNA, Neoplasm - genetics; Sarcoma; STAT1 Transcription Factor - metabolism; Sulfones - pharmacology; Up-Regulation - radiation effects; X ray irradiation; X-Rays; high linear energy transfer (LET) carbon-ion therapy; PD-L1 expression; DNA damage response; anti-PD-1/PD-L1 therapy
• ISSN: 0449-3060; 1349-9157; 1349-9157
• DOI: 10.1093/jrr/rrab050

Programmed death ligand 1 (PD-L1) expression on the surface of cancer cells affects the efficacy of anti-PD-1/PD-L1 immune checkpoint therapy. However, the mechanism underlying PD-L1 expression in cancer cells is not fully understood, particularly after ionizing radiation (IR). Here, we examined the impact of high linear energy transfer (LET) carbon-ion irradiation on the expression of PD-L1 in human osteosarcoma U2OS cells. We found that the upregulation of PD-L1 expression after high LET carbon-ion irradiation was greater than that induced by X-rays at the same physical and relative biological effectiveness (RBE) dose, and that the upregulation of PD-L1 induced by high LET carbon-ion irradiation was predominantly dependent on ataxia telangiectasia and Rad3-related (ATR) kinase activity. Moreover, we showed that the downstream signaling, e.g. STAT1 phosphorylation and IRF1 expression, was upregulated to a greater extent after high LET carbon-ion irradiation than X-rays, and that IRF1 upregulation was also ATR dependent. Finally, to visualize PD-L1 molecules on the cell surface in 3D, we applied immunofluorescence-based super-resolution imaging. The three-dimensional structured illumination microscopy (3D-SIM) analyses revealed substantial increases in the number of presented PD-L1 molecules on the cell surface after high LET carbon-ion irradiation compared with X-ray irradiation.