Molecular mechanism of PD-L1 upregulation in cancer cells after DNA double-strand break repair pathway following irradiation

• Project/Area Number: 17K16420
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Radiation science
• Research Institution: Gunma University
• Principal Investigator: Sato Hiro 群馬大学, 重粒子線医学推進機構, 助教 (90750571)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 放射線治療 / 免疫チェックポイント / DNA二本鎖切断 / 放射線腫瘍免疫 / 炭素イオン線照射 / X線照射 / 放射線 / 腫瘍免疫

Outline of Final Research Achievements

DNA damage signal-dependent PD-L1 induction was observed after X-ray irradiation and chemotherapeutic agent treatment. In addition, DNA damage signal-dependent PD-L1 expression was enhanced via Chk1 activation in Ku80 or BRCA2 knockdown cancer cells. These data revealed that Chk1 activation is important for PD-L1 induction after DNA damage. Furthermore, the STAT1 / 3-IRF1 pathway is also involved in the induction of PD-L1 expression by DNA double strand breaks.
Taken together, the mechanism by which the DNA damage response is involved in the regulation of PD-L1 expression in tumor cells was elucidated.

Academic Significance and Societal Importance of the Research Achievements

本研究にて、腫瘍細胞のPD-L1発現に影響するDNA修復関連遺伝子を明らかにしたことで、患者一人ひとりのDNA修復関連遺伝子の変異状況の評価により、放射線治療や化学療法と抗PD-1/PD-L1抗体を併用した場合の効果予測が可能となり、患者の個人レベルでの治療効果の改善に貢献できると考えている。さらに、抗PD-1抗体の医療費は高額であることから、放射線治療と抗PD-1抗体治療併用の症例毎の有効性の予測は、医療費における経済的メリットにも繋がると考えられる。

Research Products

• [Journal Article] Base excision repair regulates PD-L1 expression in cancer cells (2019)
  • Author(s): Permata, MBT, Hagiwara, Y., Sato, H., Yasuhara, T., Oike, T., Gondhowiardjo, S., Held, KD, Nakano, T., and Shibata, A.
  • Journal Title: Oncogene Volume: 印刷中 Issue: 23 Pages: 4452-4466
  • DOI: 10.1038/s41388-019-0733-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Novel Approaches to Improve the Efficacy of Immuno-Radiotherapy (2019)
  • Author(s): Shevtsov Maxim, Sato Hiro, Multhoff Gabriele, Shibata Atsushi
  • Journal Title: Frontiers in Oncology Volume: －
  • DOI: 10.3389/fonc.2019.00156
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Analysis of programmed death-ligand 1 expression in primary normal human dermal fibroblasts after DNA damage (2018)
  • Author(s): Hagiwara Yoshihiko, Sato Hiro, Permata Tiara Bunga Mayang, Niimi Atsuko, Yamauchi Motohiro, Oike Takahiro, Nakano Takashi, Shibata Atsushi
  • Journal Title: Human Immunology Volume: 79 Issue: 8 Pages: 627-631
  • DOI: 10.1016/j.humimm.2018.05.008
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells (2017)
  • Author(s): Sato Hiro、Niimi Atsuko、Yasuhara Takaaki、Permata Tiara Bunga Mayang、Hagiwara Yoshihiko、Isono Mayu、Nuryadi Endang、Sekine Ryota、Oike Takahiro、Kakoti Sangeeta、Yoshimoto Yuya、Held Kathryn D.、Suzuki Yoshiyuki、Kono Koji、Miyagawa Kiyoshi、Nakano Takashi、Shibata Atsushi
  • Journal Title: Nature Communications Volume: 8 Issue: 1 Pages: 1751-1751
  • DOI: 10.1038/s41467-017-01883-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] DNA二重鎖切断修復経路による腫瘍細胞のPD-L1発現制御メカニズムの解明 (2018)
  • Author(s): 佐藤浩央
  • Organizer: 日本医学放射線腫瘍学会
  • Invited
• [Presentation] 抗PD-1/PD-L1抗体治療と放射線治療の併用療法の確立を目指した生物学的研究 (2018)
  • Author(s): 佐藤浩央
  • Organizer: 日本臨床腫瘍学会
  • Invited
• [Presentation] 放射線誘発 DNA 損傷によって誘導される腫瘍細胞のPD-L1 発現制御機構 (2018)
  • Author(s): 佐藤浩央、Tiara Bunga Mayang Permata、安原崇哲、萩原慶彦、Endang Nuryadi、尾池貴洋、吉本由哉、鈴木義行、河野浩二、宮川清、 中野隆史、柴田淳史
  • Organizer: 日本放射線腫瘍学会 生物部会
• [Presentation] 放射線により誘導される腫瘍細胞上PD-L1発現に関する分子機構の解明 (2018)
  • Author(s): 佐藤浩央
  • Organizer: 日本放射線外科学会学術集会
• [Presentation] Translational research to improve carbon ion therapy (2018)
  • Author(s): Sato Hiro
  • Organizer: GIERSH International symposium
  • Int'l Joint Research / Invited
• [Presentation] 放射線により誘導される腫瘍細胞上PD-L1発現に関する分子機構の解明. (2017)
  • Author(s): 佐藤浩央
  • Organizer: 第9回 日本放射線外科学会学術集会
• [Presentation] 放射線射線により誘導される腫瘍細胞上PD-L1発現に関する分子機構の解明. (2017)
  • Author(s): 佐藤浩央
  • Organizer: 日本放射線腫瘍学会第30回学術大会
• [Presentation] Molecular mechanism of PD-L1 upregulation in cancer cells after X-ray irradiation. (2017)
  • Author(s): Sato H, Niimi A, Yasuhara T, Isono M, Oike T, Nuryadi E, Kakoti S, Yoshimoto Y, Held KD, Suzuki Y, Kono K, Miyagawa K, Nakano T, Shibata A.
  • Organizer: ASTRO’s 59th Annual Meeting.
  • Int'l Joint Research
• [Presentation] NA repair pathway regulates PD-L1 expression in cancer cells. (2017)
  • Author(s): Sato H, Niimi A, Yasuhara T, Isono M, Permata TBM, Sekine R, Oike T, Nuryadi E, Kakoti S. Yoshimoto Y, Held KD, Suzuki Y, Kono K, Miyagawa K, Nakano T, Shibata A.
  • Organizer: 免疫多様性とがん治療 国際シンポジウム
  • Int'l Joint Research
• [Presentation] Molecular mechanism of PD-L1 expression induced by X-ray irradiation. (2017)
  • Author(s): Sato H, Niimi A, Isono M, Nakano T, Shibata A.
  • Organizer: The 7th International Society of Radiation Neurobiology Conference.
  • Int'l Joint Research