Identification of genomic structural variations leading to high expression of immune checkpoint molecules in cancer cells and establishment of detection method

• Project/Area Number: 17K07205
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor diagnostics
• Research Institution: Japanese Foundation for Cancer Research
• Principal Investigator: Sakata Seiji 公益財団法人がん研究会, がん研究所 分子標的病理プロジェクト, 研究員 (00617433)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: バイオマーカー / 免疫チェックポイント分子 / 構造異常

Outline of Final Research Achievements

Structural variations of the PD-L1 gene were frequently observed in cancers showing strong or abnormal expression of PD-L1 by immunostaining. We identified disruption of the PD-L1 3'-untranslated region (3'-UTR) in 17 lymphoma samples, 1 colon cancer sample, and 1 gynecologic cancer sample. We found PD-L2 high expression in 13 lymphoma specimens by immunohistochemistry, and abnormal signals were observed in all of them by fluorescence in situ hybridization. We are investigating the detection method of disruption of the PD-L1 3'-UTR by expression analysis.

Academic Significance and Societal Importance of the Research Achievements

PD-L1遺伝子の増幅や構造異常に伴う3´非翻訳領域の変異がPD-L1過剰発現をきたすメカニズムとして知られており、免疫チェックポイント分子自体の遺伝子異常が免疫チェックポイント阻害薬の治療効果を予測するバイオマーカーになりうると考えられている。腫瘍細胞の本質的な免疫チェックポイント分子の過剰発現をきたす遺伝子構造異常を念頭に置き、PD-L1の発現強度や発現パターンを加味し評価することでPD-L1発現をきたす遺伝子構造異常陽性例の同定が可能であり、治療効果の高い症例の検出へとつながりうる結果であった。

Research Products

• [Journal Article] Secreted PD-L1 variants mediate resistance to PD-L1 blockade therapy in non-small cell lung cancer (2019)
  • Author(s): Gong Bo, Kiyotani Kazuma, Sakata Seiji, Nagano Seiji, Kumehara Shun, Baba Satoko, Besse Benjamin, Yanagitani Noriko, Friboulet Luc, Nishio Makoto, Takeuchi Kengo, Kawamoto Hiroshi, Fujita Naoya, Katayama Ryohei
  • Journal Title: The Journal of Experimental Medicine Volume: 216 Issue: 4 Pages: 982-1000
  • DOI: 10.1084/jem.20180870
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Frequent structural variations involving programmed death ligands in Epstein-Barr virus-associated lymphomas (2019)
  • Author(s): Kataoka Keisuke, Miyoshi Hiroaki, Sakata Seiji, Dobashi Akito, Couronne Lucile, Kogure Yasunori, Sato Yasuharu, Nishida Kenji, Gion Yuka, Shiraishi Yuichi, Tanaka Hiroko, et al
  • Journal Title: Leukemia Volume: Epub ahead of print Issue: 7 Pages: 1687-1699
  • DOI: 10.1038/s41375-019-0380-5
  • Peer Reviewed / Open Access / Int'l Joint Research