Molecular mechanism of chemotherapy-induced immunosuppressive proteins expressions in esophageal cancer cells.

• Project/Area Number: 18K07319
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: The University of Tokyo
• Principal Investigator: Mika Hamada-Uematsu 東京大学, 医科学研究所, 特任研究員 (90769449)
• Co-Investigator(Kenkyū-buntansha): 田原 秀晃 東京大学, 医科学研究所, 特任教授 (70322071) ; 内田 宏昭 東京大学, 医科学研究所, 特任准教授 (20401250)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: がん免疫療法 / 免疫チェックポイント / PD-L1 / MFG-E8 / PD-L2 / 抗がん剤 / 化学免疫併用療法

Outline of Final Research Achievements

In this study, we aimed to identify mechanisms which regulate immunosuppressive proteins expressions in response to chemotherapy. We found PD-L1, PD-L2 and MFG-E8 were induced by chemotherapeutic agents treatment in the human esophageal cancer cell line TE-11 and the breast cancer cell line MDA-MB-231 using flow cytometry and real time RT-PCR. Moreover, Promoter assay with site-directed mutagenesis, chromatin immunoprecipitation assay, and knockdown experiment using siRNA revealed that chemotherapeutic agents induced PD-L1 and MFG-E8 expressions via transcriptional factor Y in TE-11. These results indicate that transcriptional factor Y is primarily responsible for the chemotherapeutic agent-induced immunosuppressive protein regulation in esophageal cancer cells.

Academic Significance and Societal Importance of the Research Achievements

抗がん剤刺激によるPD-L1, MFG-E8の発現亢進に転写因子Yが関与するという結果は新規の知見である。また本研究課題の核心をなす学術的問いである「がん細胞は、抗がん剤に対する総合的防御機構の構成要素として免疫逃避能を有しているのか？」に対し、「転写因子Yを介した総合的防御機構に免疫逃避能も含まれる」という解を得た。
がん組織での転写因子Yの発現量により化学療法後の免疫逃避因子の発現パターンが推察でき、化学免疫併用療法の効果予測や治療法選択の一助になることが示唆された。さらに転写因子Yをターゲットとした薬剤と免疫療法の併用等、がん細胞の総合的防御機構に着目した新規治療戦略に発展できると考える。

Research Products

• [Journal Article] Potent anti-tumor effects of receptor-retargeted syncytial oncolytic herpes simplex virus (2021)
  • Author(s): Suzuki Takuma、Uchida Hiroaki、Shibata Tomoko、Sasaki Yasuhiko、Ikeda Hitomi、Hamada-Uematsu Mika、Hamasaki Ryota、Okuda Kosaku、Yanagi Shigeru、Tahara Hideaki
  • Journal Title: Molecular Therapy - Oncolytics Volume: 22 Pages: 265-276
  • DOI: 10.1016/j.omto.2021.08.002
  • Peer Reviewed / Open Access
• [Journal Article] Antibody Screening System Using a Herpes Simplex Virus (HSV)-Based Probe To Identify a Novel Target for Receptor-Retargeted Oncolytic HSVs (2021)
  • Author(s): Hitomi Ikeda, Hiroaki Uchida, Yu Okubo, Tomoko Shibata, Yasuhiko Sasaki, Takuma Suzuki, Mika Hamada -Uematsu, Ryota Hamasaki, Kosaku Okuda, Miki Yamaguchi, Masaki Kojima, Masato Tanaka, Hirofumi Hamada, Hideaki Tahara
  • Journal Title: Journal of Virology Volume: 95 Issue: 9
  • DOI: 10.1128/jvi.01766-20
  • Peer Reviewed / Open Access
• [Journal Article] Immunoregulatory influence of abundant MFG-E8 expression by esophageal cancer treated with chemotherapy (2018)
  • Author(s): Kanemura Takashi、Miyata Hiroshi、Makino Tomoki、Tanaka Koji、Sugimura Keijiro、Hamada-Uematsu Mika、Mizote Yu、Uchida Hiroaki、Miyazaki Yasuhiro、Takahashi Tsuyoshi、Kurokawa Yukinori、Yamasaki Makoto、Wada Hisashi、Nakajima Kiyokazu、Takiguchi Shuji、Mori Masaki、Doki Yuichiro、Tahara Hideaki
  • Journal Title: Cancer Science Volume: 109 Issue: 11 Pages: 3393-3402
  • DOI: 10.1111/cas.13785
  • Peer Reviewed / Open Access
• [Presentation] Prefrontal cortex dynamics for overriding emotional responding (2019)
  • Author(s): Akira Uematsu, Mika Hamada-Uematsu, Tomoya Duenki, Kenta M. Hagihara, Andreas Luthi, Joshua Johansen
  • Organizer: NEURO 2019
  • Int'l Joint Research