Development of a novel therapeutic strategy for PTCL-NOS based on functional analysis of tumor microenvironment

• Project/Area Number: 20K17403
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Kagoshima University
• Principal Investigator: Sugio Takeshi 鹿児島大学, 医歯学総合研究科, 特別研究員PD (10870446)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2022: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 末梢性T細胞リンパ腫 / 微小環境 / 遺伝子発現解析 / イメージングマスサイトメトリー / cfDNA / 悪性リンパ腫 / 免疫チェックポイント阻害薬 / 血漿中核酸 / オルガノイド / single-cell RNA-Seq

Outline of Research at the Start

末梢性T細胞リンパ腫非特定型(PTCL-NOS)はT細胞リンパ腫の中でも頻度が高く予後不良な病型である。申請者は先行研究で、PTCL-NOSを微小環境因子によって再分類し、新規予後層別化モデルを確立した(Sugio: Blood adv. 2018)。
本研究では、腫瘍組織の新規三次元培養技術や、多次元イメージングマスサイトメトリーを用いることで、微小環境因子の機能解析を行う。
本研究を行うことで、微小環境因子が予後を規定するメカニズムを解明し、新規治療戦略の開発を行う。さらに、本研究で開発する疾患モデルを用いて前臨床治験段階の新規薬剤のスクリーニングも行い、効率よい臨床治験の計画に繋げる。

Outline of Final Research Achievements

Gene expression analysis of peripheral T-cell lymphoma (PTCL) tumor tissues showed that the patients could be classified into four groups according to microenvironment-related gene expression, and the Macrophage-rich and NME groups (low expression of B-cell and dendritic cell-related genes) had a poor prognosis. Macrophage-rich cases had high expression level of PD-L1 and NME patients had high expression level of BIRC5. BIRC5 inhibition by inhibitor and gene modification was effective in inhibiting tumor growth in both in vitro and vivo disease models. After microenvironmental profiling of a few cases by imaging mass cytometry, we noticed a large heterogeneity in the same cases and within the same tissues. As a result, we developed a comprehensive evaluation method of immune microenvironment using cfDNA.

Academic Significance and Societal Importance of the Research Achievements

本研究において、PTCLという希少かつ予後不良な疾患が微小環境関連遺伝子発現によって分類でき、予後層別化できることを検証した。さらにその分類に基づいた予後不良症例に対する新規治療標的の候補も同定した。今後の臨床試験の計画、予後改善のために有用であることから意義深いと考えられる。さらに、cfDNAを用いた微小環境評価法の開発を行なっているが、非侵襲的にかつ経時的に評価可能な系であり、社会的意義も大きいと考えられる。

Research Products

• [Int'l Joint Research] Stanford University(米国)
• [Journal Article] Short-term methotrexate plus cyclosporine for graft-versus-host disease prophylaxis after single-unit cord blood transplantation following reduced-intensity conditioning (2022)
  • Author(s): Sugio Takeshi、Kato Koji、Yoshida Shuro、Saito Noriyuki、Kawano Ichiro、Henzan Hideho、Miyamoto Toshihiro、Akashi Koichi、Eto Tetsuya
  • Journal Title: Japanese Journal of Transplantation and Cellular Therapy Volume: 11 Issue: 1 Pages: 64-71
  • DOI: 10.7889/tct-21-001
  • NAID: 130008142095
  • ISSN: 2436-455X
  • Peer Reviewed
• [Journal Article] Targeting leukemia-specific dependence on the de novo purine synthesis pathway. (2022)
  • Author(s): Yamauchi T, Miyawaki K, Semba Y, Takahashi M, Izumi Y, Nogami J, Nakao F, Sugio T, Sasaki K, Pinello L, Bauer DE, Bamba T, Akashi K, Maeda T*.
  • Journal Title: Leukemia Volume: 36(2) Issue: 2 Pages: 383-393
  • DOI: 10.1038/s41375-021-01369-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Germinal Center-Associated Microenvironmental Signature Reflects Malignant Phenotype and Outcome of DLBCL. (2022)
  • Author(s): Miyawaki K, Kato K, Sugio T, Sasaki K, Miyoshi H, Semba Y, Kikushige Y, Mori Y, Kunisaki Y, Iwasaki H, Miyamoto T, Kuo FC, Aster JC, Ohshima K, Maeda T, Akashi K.
  • Journal Title: Blood Adv. Volume: 6 Issue: 7 Pages: 2388-2402
  • DOI: 10.1182/bloodadvances.2021004618
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Macrophages are primed to transdifferentiate into fibroblasts in malignant ascites and pleural effusions (2022)
  • Author(s): Ito Mamoru、Nakano Michitaka、Ariyama Hiroshi、Yamaguchi Kyoko、Tanaka Risa、Semba Yuichiro、Sugio Takeshi、Miyawaki Kohta、Kikushige Yoshikane、Mizuno Shinichi、Isobe Taichi、Tanoue Kenro、Taguchi Ryosuke、Ueno Shohei、Kawano Takahito、Murata Masaharu、Baba Eishi、Akashi Koichi
  • Journal Title: Cancer Letters Volume: 532 Pages: 215597-215597
  • DOI: 10.1016/j.canlet.2022.215597
  • Peer Reviewed
• [Journal Article] Prognostic value of pre-transplantation total metabolic tumor volume on 18fluoro-2-deoxy-d-glucose positron emission tomography-computed tomography in relapsed and refractory aggressive lymphoma (2022)
  • Author(s): Takeshi Sugio、Shingo Baba、Yasuo Mori、Goichi Yoshimoto、Kenjiro Kamesaki、Shuichiro Takashima、Shingo Urata、Takahiro Shima、Kohta Miyawaki、Yoshikane Kikushige、Yuya Kunisaki、Akihiko Numata、Katsuto Takenaka、Hiromi Iawasaki、Toshihiro Miyamoto、Kousei Ishigami、Koichi Akashi、Koji Kato
  • Journal Title: International Journal of Hematology Volume: -
• [Journal Article] Platelet decrease and efficacy of platelet‐rich plasma return following peripheral blood stem cell apheresis (2021)
  • Author(s): Shima Takahiro、Sakoda Teppei、Henzan Tomoko、Kunisaki Yuya、Sugio Takeshi、Kamezaki Kenjiro、Iwasaki Hiromi、Teshima Takanori、Maeda Takahiro、Akashi Koichi、Miyamoto Toshihiro
  • Journal Title: Journal of Clinical Apheresis Volume: 36 Issue: 5 Pages: 687-696
  • DOI: 10.1002/jca.21917
  • Peer Reviewed
• [Journal Article] Ustekinumab improves active Crohn’s disease by suppressing the T Helper 17 pathway. (2021)
  • Author(s): Ihara Y, Torisu T, Miyawaki K, Umeno J, Kawasaki K, Hirano A, Fujioka S, Fuyuno Y, Matsuno Y, Sugio T, Sasaki K, Moriyama T, Akashi K, Kitazono T
  • Journal Title: Digestion Volume: 102 Issue: 6 Pages: 946-955
  • DOI: 10.1159/000518103
  • Peer Reviewed
• [Journal Article] B cell receptor signaling related to resistance to Helicobacter pylori eradication therapy in gastric diffuse large B cell lymphoma (2020)
  • Author(s): Torisu Takehiro、Kawano Shinichi、Miyawaki Kohta、Yamamoto Hidetaka、Ihara Yutaro、Matsuno Yuichi、Torisu Kumiko、Sugio Takeshi、Sasaki Kensuke、Shimakawa Takashi、Kato Koji、Akashi Koichi、Nakamura Shotaro、Kitazono Takanari
  • Journal Title: Hematological Oncology Volume: 39 Issue: 1 Pages: 145-147
  • DOI: 10.1002/hon.2816
  • Peer Reviewed / Open Access
• [Journal Article] Outcome predictors after retransplantation in relapsed acute lymphoblastic leukemia: a multicenter, retrospective study (2020)
  • Author(s): Mori Yasuo、Fukuoka Blood and Marrow Transplantation Group、Sasaki Kensuke、Ito Yoshikiyo、Kuriyama Takuro、Ueno Toshiyuki、Kadowaki Masanori、Aoki Takatoshi、Sugio Takeshi、Yoshimoto Goichi、Kato Koji、Maeda Takahiro、Nagafuji Koji、Akashi Koichi、Miyamoto Toshihiro
  • Journal Title: Annals of Hematology Volume: 100 Issue: 1 Pages: 197-208
  • DOI: 10.1007/s00277-020-04310-0
  • Peer Reviewed / Open Access
• [Presentation] Immunogenicity of mismatched HLA is correlated with outcomes of cord blood transplantation (2021)
  • Author(s): 杉尾健志
  • Organizer: 第83回日本血液学会
• [Presentation] T細胞リンパ腫における免疫微小環境 (2020)
  • Author(s): 杉尾健志
  • Organizer: 第60回日本リンパ網内系学会総会
  • Invited