Elucidation of molecular mechanism of the regulation of PD-L1 expression by histone methylation

• Project/Area Number: 17K14994
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: National Hospital Organization, Kyushu Medical Center (Clinical Institute) (2018-2019); Kyushu University (2017)
• Principal Investigator: Toyokawa Gouji 独立行政法人国立病院機構九州医療センター(臨床研究センター), その他部局等, 呼吸器外科医師 (30627261)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: PD-L1 / EZH2 / 肺癌 / 免疫療法 / 肺腺癌 / 手術 / 免疫学

Outline of Final Research Achievements

A total of 428 patients with resected lung adenocarcinoma were analyzed for their EZH2 and PD-L1 expression by immunohistochemistry and evaluated to determine the association between the EZH2 and PD-L1 expression. Patients with the EZH2-positive lung adenocarcinoma exhibited a significantly higher expression of PD-L1 than those without it. A logistic regression analysis with backward elimination revealed that PD-L1 positivity was independently associated with the EZH2 expression. This result was published in 2019 (Annals of Thoracic Surgery). This study provides the first evidence of a possible association between the EZH2 and PD-L1 expression in patients with resected lung adenocarcinoma.
The PD-L1 expression at the mRNA level was not significantly decreased by the siRNA-mediated knockdown of EZH2 in comparison to siRNA normal control in the cellular level; therefore, the protein stability and subcellular localization of PD-L1 by EZH2 should be investigated in future studies.

Academic Significance and Societal Importance of the Research Achievements

PD-L1とEZH2の関連についての報告はなく、本研究が世界初の報告である。免疫チェックポイント阻害剤の標的であり、かつ効果予測因子でもあるPD-L1と、代表的なヒストンメチル化酵素であるEZH2との関連を示した点で、非常に意義があるものと考える。本知見はニボルマブやアテゾリズマブなどの免疫チェックポイント阻害剤へのEZH2阻害剤の上乗せ効果の可能性を示唆するものである。

Research Products

• [Journal Article] A Positive Correlation Between the EZH2 and PD-L1 Expression in Resected Lung Adenocarcinomas (2019)
  • Author(s): Toyokawa Gouji、Takada Kazuki、Tagawa Tetsuzo、Hamamoto Ryuji、Yamada Yuichi、Shimokawa Mototsugu、Oda Yoshinao、Maehara Yoshihiko
  • Journal Title: The Annals of Thoracic Surgery Volume: 107 Issue: 2 Pages: 393-400
  • DOI: 10.1016/j.athoracsur.2018.08.056
  • Peer Reviewed
• [Presentation] 肺腺癌切除例におけるヒストンメチル化酵素EZH2とPD-L1との関連の検討 (2018)
  • Author(s): 豊川剛二、田川哲三、髙田和樹、木下郁彦、上妻由佳、松原太一、原武直紀、髙森信吉、赤嶺貴紀、平井文彦、前原喜彦
  • Organizer: 第118回日本外科学会定期学術集会
• [Presentation] A positive correlation between EZH2 and PD-L1 expression in resected lung adenocarcinomas (2018)
  • Author(s): Gouji Toyokawa, Kazuki Takada, Yuichi Yamada, Tetsuzo Tagawa, Fumihiro Shoji, Koji Yamazaki, Sadanori Takeo, Yoshinao Oda
  • Organizer: European Society of Medical Oncology, 2018
  • Int'l Joint Research
• [Presentation] 肺腺癌切除例におけるヒストンメチル化酵素EZH2とPD-L1との関連の検討 (2018)
  • Author(s): 豊川剛二
  • Organizer: 第118回日本外科学会定期学術集会