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Eludation of organ tropism from the diversity of malignant lymphoma and its application to novel treatment

Research Project

Project/Area Number 20K08751
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54010:Hematology and medical oncology-related
Research InstitutionNagoya University

Principal Investigator

Shimada Kazuyuki  名古屋大学, 医学部附属病院, 講師 (50631503)

Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords悪性リンパ腫 / 微小環境 / がん関連線維芽細胞 / エクソソーム / ヒストン脱アセチル化阻害薬 / 中枢神経病変 / ピリミジン拮抗薬 / 臓器指向性
Outline of Research at the Start

悪性リンパ腫は、リンパ節を病変の主座とする節性リンパ腫、節外臓器を病変の主座とする節外性リンパ腫に大別される。本研究では、節性リンパ腫病変においては、微小環境を構成するがん関連線維芽細胞(CAF)より分泌されるエクソソームに焦点をおき、エクソソームがもたらす腫瘍細胞への薬剤感受性変化および周囲の免疫担当細胞への影響について検討する。節外性リンパ腫病変においては、これまでの検討で見出した中枢神経病変に強発現する遺伝子の機能を解析するとともに、中枢神経病変形成に関連する腫瘍細胞のクローン性について検討する。また血管内病変を形成する血管内リンパ腫に対する新たな免疫療法の可能性を探索する。

Outline of Final Research Achievements

In this study, we elucidated that exosomes from cancer associated fibroblasts (CAFs) derived from nodal lesion of malignant lymphoma elicited anti-pyrimidine drugs resistance such as cytarabine and gemcitabine through modulation of it transporter. In addition, we also elucidated that cytokines secreted from CAFs enhanced antibody dependent cytotoxicity of anti-CD20 monoclonal antibody, while exosomes induced the resistance to HDAC inhibitor. Moreover, we demonstrated the efficacy of anti-PD-1 monoclonal antibody in PD-L1 positive tumor in patient xenograft mouse model established from an intractable intravascular large B-cell lymphoma patient.

Academic Significance and Societal Importance of the Research Achievements

悪性リンパ腫の節性病変を構成するCAFより分泌されるサイトカインやエクソソームが免疫担当細胞の抗体依存性細胞傷害活性の増強、腫瘍細胞の抗がん薬耐性化の獲得など様々な生理作用に関与する可能性を示したことは、悪性リンパ腫の多様性のある病態を理解する一助となり学術的意義があると考えられる。また、難治性悪性リンパ腫患者由来異種移植マウスモデルにおいても抗PD-1抗体医薬の薬効が確認出来たことは、難治性病態に対するPD-L1を標的とする治療応用への可能性に繋がる点で意義深いと考えられる。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (27 results)

All 2022 2021 2020 Other

All Journal Article (17 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 17 results,  Open Access: 12 results) Presentation (9 results) (of which Int'l Joint Research: 1 results,  Invited: 5 results) Remarks (1 results)

  • [Journal Article] Long‐term outcomes and central nervous system relapse in extranodal natural killer/T‐cell lymphoma2022

    • Author(s)
      Miyazaki K, Suzuki R, Oguchi M, Taguchi S, ..., Yamaguchi M
    • Journal Title

      Hematol Oncol

      Volume: 40 Issue: 4 Pages: 667-677

    • DOI

      10.1002/hon.2977

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A phase 2 study of axicabtagene ciloleucel in relapsed or refractory large B-cell lymphoma in Japan: 1-year follow-up and biomarker analysis2022

    • Author(s)
      Kato Koji、Fujii Nobuharu、Makita Shinichi、Goto Hideki、Kanda Junya、Shimada Kazuyuki、Akashi Koichi、Izutsu Koji、Teshima Takanori、Fukuda Natsuko、Sumitani Tokuhito、Nakamura Shota、Sumi Hiroyuki、Shimizu Shinji、Kakurai Yasuyuki、Yoshikawa Kenji、Tobinai Kensei、Usui Noriko、Hatake Kiyohiko
    • Journal Title

      International Journal of Hematology

      Volume: 117 Issue: 3 Pages: 409-420

    • DOI

      10.1007/s12185-022-03494-7

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma in the Gastrointestinal Tract in the Modern Era2022

    • Author(s)
      Ishikawa Eri、Nakamura Masanao、Satou Akira、Shimada Kazuyuki、Nakamura Shotaro
    • Journal Title

      Cancers

      Volume: 14 Issue: 2 Pages: 446-446

    • DOI

      10.3390/cancers14020446

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Diagnostic utility of programmed cell death ligand 1 (clone SP142) immunohistochemistry for malignant lymphoma and lymphoproliferative disorders: A brief review2021

    • Author(s)
      Sakakibara Ayako、Kohno Kei、Ishikawa Eri、Suzuki Yuka、Tsuyuki Yuta、Shimada Satoko、Shimada Kazuyuki、Satou Akira、Takahara Taishi、Ohashi Akiko、Takahashi Emiko、Kato Seiichi、Nakamura Shigeo、Asano Naoko
    • Journal Title

      Journal of Clinical and Experimental Hematopathology

      Volume: 61 Issue: 4 Pages: 182-191

    • DOI

      10.3960/jslrt.21003

    • NAID

      130008131970

    • ISSN
      1346-4280, 1880-9952
    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clinicopathologic Analysis of Primary Adrenal Diffuse Large B-Cell Lymphoma2021

    • Author(s)
      Kawano Tasuku、Tsuyuki Yuta、Suzuki Yuka、Shimada Kazuyuki、Kato Seiichi、Takahara Taishi、Mori Mayuko、Nakaguro Masato、Sakakibara Ayako、Nakamura Shigeo、Satou Akira
    • Journal Title

      American Journal of Surgical Pathology

      Volume: 45 Issue: 12 Pages: 1606-1615

    • DOI

      10.1097/pas.0000000000001809

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Current progress and future perspectives of research on intravascular large B‐cell lymphoma2021

    • Author(s)
      Shimada Kazuyuki、Kiyoi Hitoshi
    • Journal Title

      Cancer Science

      Volume: 112 Issue: 10 Pages: 3953-3961

    • DOI

      10.1111/cas.15091

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Current status of diagnosis and treatment in diffuse large B-cell lymphoma2021

    • Author(s)
      島田 和之
    • Journal Title

      Rinsho Ketsueki

      Volume: 62 Issue: 8 Pages: 1077-1084

    • DOI

      10.11406/rinketsu.62.1077

    • NAID

      130008086004

    • ISSN
      0485-1439, 1882-0824
    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Follicular T-cell lymphoma mimicking lymphocyte-rich classic Hodgkin lymphoma: a case report of a diagnostic pitfall2021

    • Author(s)
      Sakakibara Ayako、Suzuki Yuka、Kato Harumi、Yamamoto Kazuhito、Sakata-Yanagimoto Mamiko、Ishikawa Yuichi、Furukawa Katsuya、Shimada Kazuyuki、Kohno Kei、Nakamura Shigeo、Satou Akira、Kato Seiichi
    • Journal Title

      Journal of Clinical and Experimental Hematopathology

      Volume: 61 Issue: 2 Pages: 97-101

    • DOI

      10.3960/jslrt.20052

    • NAID

      130008049329

    • ISSN
      1346-4280, 1880-9952
    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The Positivity of Phosphorylated STAT3 Is a Novel Marker for Favorable Prognosis in Germinal Center B-Cell Type of Diffuse Large B-Cell Lymphoma2021

    • Author(s)
      K. Morichika, K. Karube, S. Sakihama, R. Watanabe, M. Kawaki, Y. Nishi, S. Nakachi, S. Okamoto, T. Takahara, A. Satou, S. Shimada, K. Shimada, T. Tsuzuki, T. Fukushima, S. Morishima and H. Masuzaki
    • Journal Title

      Am J Surg Pathol

      Volume: - Issue: 6 Pages: 832-840

    • DOI

      10.1097/pas.0000000000001691

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 血管内大細胞型B細胞リンパ腫研究の現状と今後の展望2021

    • Author(s)
      島田 和之
    • Journal Title

      臨床血液

      Volume: 62 Pages: 631-640

    • NAID

      130008061915

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Spacer Length Modification Facilitates Discrimination between Normal and Neoplastic Cells and Provides Clinically Relevant CD37 CAR T Cells2021

    • Author(s)
      Okuno Shingo、Adachi Yoshitaka、Terakura Seitaro、Julamanee Jakrawadee、Sakai Toshiyasu、Umemura Koji、Miyao Kotaro、Goto Tatsunori、Murase Atsushi、Shimada Kazuyuki、Nishida Tetsuya、Murata Makoto、Kiyoi Hitoshi
    • Journal Title

      The Journal of Immunology

      Volume: 206 Issue: 12 Pages: 2862-2874

    • DOI

      10.4049/jimmunol.2000768

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Exosomes secreted from cancer-associated fibroblasts elicit anti-pyrimidine drug resistance through modulation of its transporter in malignant lymphoma.2021

    • Author(s)
      Kunou S, Shimada K, Takai M, Sakamoto A, Aoki T, Hikita T, Kagaya Y, Iwamoto E, Sanada M, Shimada S, Hayakawa F, Oneyama C, Kiyoi H.
    • Journal Title

      Oncogene

      Volume: 40 Issue: 23 Pages: 3989-4003

    • DOI

      10.1038/s41388-021-01829-y

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Frequent genetic alterations in immune checkpoint-related genes in intravascular large B-cell lymphoma2021

    • Author(s)
      Shimada Kazuyuki、Yoshida Kenichi、Suzuki Yasuhiro、Iriyama Chisako、Inoue Yoshikage、Sanada Masashi、Kataoka Keisuke、Yuge Masaaki、Takagi Yusuke、Kusumoto Shigeru、Masaki Yasufumi、Ito Takahiko、Inagaki Yuichiro、Okamoto Akinao、Kuwatsuka Yachiyo、Nakatochi Masahiro、Shimada Satoko、Miyoshi Hiroaki et al.
    • Journal Title

      Blood

      Volume: 137 Issue: 11 Pages: 1491-1502

    • DOI

      10.1182/blood.2020007245

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] PD‐L1 (SP142) expression in neoplastic cells predicts a poor prognosis for patients with intravascular large B‐cell lymphoma treated with rituximab‐based multi‐agent chemotherapy2020

    • Author(s)
      Suzuki Yuka、Kohno Kei、Matsue Kosei、Sakakibara Ayako、Ishikawa Eri、Shimada Satoko、Shimada Kazuyuki、Mabuchi Seiyo、Takahara Taishi、Kato Seiichi、Nakamura Shigeo、Satou Akira
    • Journal Title

      Cancer Medicine

      Volume: 9 Issue: 13 Pages: 4768-4776

    • DOI

      10.1002/cam4.3104

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] PD‐L1 expression on tumor or stromal cells of nodal cytotoxic T‐cell lymphoma: A clinicopathological study of 50 cases2020

    • Author(s)
      Yamashita Daisuke、Shimada Kazuyuki、Kohno Kei、Kogure Yasunori、Kataoka Keisuke、Takahara Taishi、Suzuki Yuka、Satou Akira、Sakakibara Ayako、Nakamura Shigeo、Asano Naoko、Kato Seiichi
    • Journal Title

      Pathology International

      Volume: 70 Issue: 8 Pages: 513-522

    • DOI

      10.1111/pin.12950

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Reappraisal of Primary Epstein-Barr Virus (EBV)-positive Diffuse Large B-Cell Lymphoma of the Gastrointestinal Tract2020

    • Author(s)
      Miyagi Shouhei、Ishikawa Eri、Nakamura Masanao、Shimada Kazuyuki、Yamamura Takeshi、Furukawa Kazuhiro、Tanaka Tsutomu、Mabuchi Seiyo、Tsuyuki Yuta、Kohno Kei、Sakakibara Ayako、Satou Akira、Kato Seiichi、Fujishiro Mitsuhiro、Nakamura Shigeo
    • Journal Title

      American Journal of Surgical Pathology

      Volume: 44 Issue: 9 Pages: 1173-1183

    • DOI

      10.1097/pas.0000000000001499

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Expression of programmed cell death ligand‐1 by immune cells in the microenvironment is a favorable prognostic factor for primary diffuse large B‐cell lymphoma of the central nervous system2020

    • Author(s)
      Tsuyuki Yuta、Ishikawa Eri、Kohno Kei、Shimada Kazuyuki、Ohka Fumiharu、Suzuki Yuka、Mabuchi Seiyo、Satou Akira、Takahara Taishi、Kato Seiichi、Miyagi Shohei、Ozawa Hiroyuki、Kawano Tasuku、Takagi Yusuke、Hiraga Junji、Wakabayashi Toshihiko、Nakamura Shigeo
    • Journal Title

      Neuropathology

      Volume: 41 Issue: 2 Pages: 99-108

    • DOI

      10.1111/neup.12705

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Presentation] IVLBCLに対するBTK阻害薬のpreclinical modelにおける有効性2022

    • Author(s)
      高井美佳、島田和之、清井仁
    • Organizer
      第81回日本癌学会学術総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 再発・難治性DLBCL治療のパラダイムシフト2022

    • Author(s)
      島田和之
    • Organizer
      第62回日本リンパ網内系学会学術集会・総会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] リンパ形質細胞性リンパ腫/原発性マクログロブリン血症の治療2022

    • Author(s)
      島田和之
    • Organizer
      第47回日本骨髄腫学会学術集会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Clinical Outcomes of Elderly Patients with Advanced-Stage Classic Hodgkin Lymphoma Who Received an ABVD Regimen: A Multi-Center Retrospective Study in Japan (HORIZON study)2021

    • Author(s)
      Makita S, Kusumoto S, Maeshima-Miyagi A, Hashimoto H, Tsujimura H, Uchida T, Inoue H, Ohtsuka E, Kurosawa M, Takayama N, Negoro E, Suzuki Y, Kuroda J, Murayama K, Takahashi N, Shimada K, Okamoto M, Makita M, Iwasaki H, Yoshida M, Asano N, Tamaru J, Maruyama D, Yamaguchi M, Nagai H
    • Organizer
      63rd ASH Annual Meeting and Exposition.
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] 血管内大細胞型B細胞リンパ腫~これまでの研究の到達点と今後の展望~2021

    • Author(s)
      島田和之
    • Organizer
      第95回日本病理学会近畿支部学術講演会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] びまん性大細胞型B細胞リンパ腫の治療戦略2021

    • Author(s)
      島田和之
    • Organizer
      第83回日本血液学会学術集会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] Exosomes derived from cancer associated fibroblasts induce a resistance to histone deacetylase inhibitors in lymphoma.2020

    • Author(s)
      加賀谷裕介、島田和之、久納俊祐、疋田智也、青木智広、坂本明彦、早川文彦、小根山千歳、清井仁.
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Research-status Report
  • [Presentation] Current achievement of research and clinical practice in intravascular large B-cell lymphoma2020

    • Author(s)
      島田和之
    • Organizer
      第82回日本血液学会学術集会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] NDRG2はびまん性大細胞型B細胞リンパ腫の中枢神経病変において高発現を来す2020

    • Author(s)
      村瀨篤史、島田和之、青木智広、真田昌、中杤昌弘、島田聡子、久納俊祐、中村栄男、清井仁
    • Organizer
      第82回日本血液学会学術集会
    • Related Report
      2020 Research-status Report
  • [Remarks] 診断困難な悪性リンパ腫病型における遺伝子異常を末梢血を用いて高感度に検出

    • URL

      https://www.med.nagoya-u.ac.jp/medical_J/research/pdf/Blo_201225.pdf

    • Related Report
      2020 Research-status Report

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Published: 2020-04-28   Modified: 2024-01-30  

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