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Analysis of the role of sRANKL in the bone-tumor microenvironment in immune checkpoint inhibitor treatment

Research Project

Project/Area Number 20F20730
Research Category

Grant-in-Aid for JSPS Fellows

Allocation TypeSingle-year Grants
Section外国
Review Section Basic Section 49070:Immunology-related
Research InstitutionThe University of Tokyo

Principal Investigator

高柳 広  東京大学, 大学院医学系研究科(医学部), 教授 (20334229)

Co-Investigator(Kenkyū-buntansha) ZANG SHIZHAO  東京大学, 医学(系)研究科(研究院), 外国人特別研究員
Project Period (FY) 2020-07-29 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 2021: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2020: ¥1,200,000 (Direct Cost: ¥1,200,000)
Keywordsがん骨転移 / RANKL / がん免疫 / 骨免疫学
Outline of Research at the Start

遠隔臓器への転移はがん患者の最大の死因であり、がん転移の制圧は重要な課題である。特に骨は代表的な転移標的臓器であり、骨転移後の期待余命は低く予後不良を齎す。近年、免疫チェックポイント阻害剤の登場により、がんの治療体系が大きく変革する一方、未だ骨転移に対しては効果が低くその原因も不明である。最近、破骨細胞分化必須因子RANKLの中和抗体と免疫チェックポイント阻害剤の併用療法が骨転移に対して有効であることが明らかとなり、RANKLの意外ながん免疫学的機能が指摘されつつある。そこで本課題ではRANKLによる抗腫瘍免疫応答の制御機構を明らかにし、骨転移に対する新規治療法の分子基盤の構築に取り組む。

Outline of Annual Research Achievements

ヒト骨転移巣のシングルセルRNA-seqデータを再解析することで、正常骨髄および骨転移巣微小環境内の免疫細胞亜集団を調べ、RANKやRANKL発現を指標に、骨転移巣病態に関与するRANKL発現細胞とRANK発現細胞の候補を選定した。候補細胞特異的なRANKL欠損マウス、およびRANK欠損マウスを用いてマウス乳がん細胞株EO771、メラノーマ細胞株B16F10の左心室移植によるがん骨転移モデルマウスを実施し、免疫チェックポイント阻害剤の効果を検討することで、骨転移巣の抗腫瘍免疫応答に関わるRANKL産生細胞とRANK発現細胞の特定に取り組んだ。さらにEO771及びB16F10がん骨転移モデルマウスにおいて、抗RANKL抗体単剤、免疫チェックポイント阻害剤単剤、および両者の併用療法による治療効果を比較検討し、各条件における骨転移巣部位のCD8 T細胞、CD4 T細胞、NK細胞の活性化状態・サイトカイン産生を解析することで、RANKL抑制による抗腫瘍免疫応答の変化を明らかにした。最終的に、免疫チェックポイント阻害剤投与および非投与マウスの骨転移巣、および正常骨髄から、RANKL発現免疫細胞を単離し、網羅的遺伝子発現解析を実施することで、免疫チェックポイント阻害剤がRANKL発現細胞に与える影響を遺伝子レベルで明らかにし、がん骨転移におけるRANKLによる抗腫瘍免疫応答制御の分子機構を解析した。

Research Progress Status

令和3年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和3年度が最終年度であるため、記入しない。

Report

(2 results)
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • Research Products

    (32 results)

All 2022 2021 2020 Other

All Int'l Joint Research (4 results) Journal Article (11 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 11 results,  Open Access: 8 results) Presentation (13 results) (of which Invited: 11 results) Book (2 results) Remarks (2 results)

  • [Int'l Joint Research] BSRC Alexander Fleming(ギリシャ)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] St. Petersburg State Pediatric Med Univ(ロシア連邦)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] University of Michigan(米国)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] King's College London(英国)

    • Related Report
      2020 Annual Research Report
  • [Journal Article] The transcription factor Sox4 is required for thymic tuft cell development2021

    • Author(s)
      Mino Nanami、Muro Ryunosuke、Ota Ayami、Nitta Sachiko、Lefebvre Veronique、Nitta Takeshi、Fujio Keishi、Takayanagi Hiroshi
    • Journal Title

      International Immunology

      Volume: 34 Issue: 1 Pages: 45-52

    • DOI

      10.1093/intimm/dxab098

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cytokine profile in patients with chronic non-bacterial osteomyelitis, juvenile idiopathic arthritis, and insulin-dependent diabetes mellitus2021

    • Author(s)
      Kostik Mikhail M.、Makhova Maria A.、Maletin Alexei S.、Magomedova Shamai M.、Sorokina Lybov S.、Tsukasaki Masayuki、Okamoto Kazuo、Takayanagi Hiroshi、Vasiliev Dmitriy S.、Kozlova Darya I.、Mushkin Alexander Yu.
    • Journal Title

      Cytokine

      Volume: 143 Pages: 155521-155521

    • DOI

      10.1016/j.cyto.2021.155521

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Plasma cells promote osteoclastogenesis and periarticular bone loss in autoimmune arthritis2021

    • Author(s)
      Komatsu N, Win S, Yan M, Huynh CN N, Sawa S, Tsukasaki M, Terashima A, Pluemsakunthai W, Kollias G, Nakashima T and Takayanagi H
    • Journal Title

      J Clin Invest.

      Volume: 131 Issue: 6 Pages: 1-8

    • DOI

      10.1172/jci143060

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Osteoimmunology as an intrinsic part of immunology2021

    • Author(s)
      Takayanagi Hiroshi
    • Journal Title

      International Immunology

      Volume: 33 Issue: 12 Pages: 673-678

    • DOI

      10.1093/intimm/dxab057

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The fibroblast: An emerging key player in thymic T cell selection2021

    • Author(s)
      Nitta Takeshi、Ota Ayami、Iguchi Takahiro、Muro Ryunosuke、Takayanagi Hiroshi
    • Journal Title

      Immunological Reviews

      Volume: 302 Issue: 1 Pages: 68-85

    • DOI

      10.1111/imr.12985

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] tepwise cell fate decision pathways during osteoclastogenesis at single-cell resolution.2021

    • Author(s)
      Tsukasaki M, Huynh NC, Okamoto K, Muro R, Terashima A, Kurikawa Y, Komatsu N, Pluemsakunthai W, Nitta T, Abe T, Kiyonari H, Okamura T, Sakai M, Matsukawa T, Matsumoto M, Kobayashi Y, Penninger JM, Takayanagi H
    • Journal Title

      Nat Metab

      Volume: 2 Issue: 12 Pages: 1382-1390

    • DOI

      10.1038/s42255-020-00318-y

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] RANKL as the master regulator of osteoclast differentiation2021

    • Author(s)
      Takayanagi Hiroshi
    • Journal Title

      Journal of Bone and Mineral Metabolism

      Volume: 39 Issue: 1 Pages: 13-18

    • DOI

      10.1007/s00774-020-01191-1

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Non-Epithelial Thymic Stromal Cells: Unsung Heroes in Thymus Organogenesis and T Cell Development2021

    • Author(s)
      Nitta Takeshi、Takayanagi Hiroshi
    • Journal Title

      Frontiers in Immunology

      Volume: 11 Pages: 620894-620894

    • DOI

      10.3389/fimmu.2020.620894

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Butyrophilin-like proteins display combinatorial diversity in selecting and maintaining signature intraepithelial γδ T cell compartments2020

    • Author(s)
      Jandke Anett、Melandri Daisy、Monin Leticia、Ushakov Dmitry S.、Laing Adam G.、Vantourout Pierre、East Philip、Nitta Takeshi、Narita Tomoya、Takayanagi Hiroshi、Feederle Regina、Hayday Adrian
    • Journal Title

      Nature Communications

      Volume: 11 Issue: 1 Pages: 3769-3769

    • DOI

      10.1038/s41467-020-17557-y

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Fibroblasts as a source of self-antigens for central immune tolerance2020

    • Author(s)
      Nitta Takeshi、Tsutsumi Masanori、Nitta Sachiko、Muro Ryunosuke、Suzuki Emma C.、Nakano Kenta、Tomofuji Yoshihiko、Sawa Shinichiro、Okamura Tadashi、Penninger Josef M.、Takayanagi Hiroshi
    • Journal Title

      Nature Immunology

      Volume: 21 Issue: 10 Pages: 1172-1180

    • DOI

      10.1038/s41590-020-0756-8

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] OPG Production Matters Where It Happened.2020

    • Author(s)
      Tsukasaki M, Asano T, Muro R, Huynh NC, Komatsu N, Okamoto K, Nakano K, Okamura T, Nitta T, Takayanagi H
    • Journal Title

      Cell Rep

      Volume: 32 Issue: 10 Pages: 1-10

    • DOI

      10.1016/j.celrep.2020.108124

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 骨免疫と自己免疫2022

    • Author(s)
      高柳広
    • Organizer
      IGMセミナー
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 骨免疫学から見た関節リウマチ治療の進歩2022

    • Author(s)
      高柳広
    • Organizer
      第63回九州リウマチ学会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Triangular Relationship in Arthritis Immune Cells, Synovial Fibroblasts and Bone2021

    • Author(s)
      高柳広
    • Organizer
      Triangular Relationship in Arthritis Immune Cells, Synovial Fibroblasts and Bone
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 骨免疫学と関節リウマチ治療の進歩2021

    • Author(s)
      高柳広
    • Organizer
      盛岡臨床リウマチ学術講演会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 骨免疫学「21」周年特別講演2021

    • Author(s)
      高柳広
    • Organizer
      第6回日本骨免疫学会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 骨免疫学から見た関節炎の病態と治療2021

    • Author(s)
      高柳広
    • Organizer
      第85回日本皮膚科学会東京支部学術大会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 骨免疫学による骨破壊性疾患への挑戦2021

    • Author(s)
      高柳広
    • Organizer
      第48回福岡歯科大学学会総会・学術大会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] ゲノム編集技術による遺伝子改変マウスを用い膜型RANKLと可溶型RANKLの骨免疫学的機能の解析2021

    • Author(s)
      杉田拓也、岡本一男、高柳広
    • Organizer
      第6回 日本骨免疫学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] The physiological significances of membrane-bound and soluble forms of RANKL in bone and lymph node development2021

    • Author(s)
      Takuya Sugita, Kazuo Okamoto, Tatsuo Asano, Takeshi Nitta, Hiroshi Takayanagi
    • Organizer
      第50回 日本免疫学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 骨免疫とRANKL2021

    • Author(s)
      高柳広
    • Organizer
      第30回日本リウマチ学会北海道・東北支部学術集会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 関節リウマチにおける免疫細胞と滑膜線維芽細胞のクロストーク2020

    • Author(s)
      高柳広
    • Organizer
      第64回日本リウマチ学会総会・学術集会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 骨免疫学からみた関節リウマチ治療2020

    • Author(s)
      高柳広
    • Organizer
      第29回田園都市リウマチフォーラム
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 骨免疫と自己免疫2020

    • Author(s)
      高柳広
    • Organizer
      Abatacept EXPERT SEMINAR
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Book] 実験医学「胸腺線維芽細胞による中枢性免疫寛容の制御」2021

    • Author(s)
      新田剛、高柳広
    • Publisher
      羊土社
    • Related Report
      2021 Annual Research Report
  • [Book] 感染 炎症 免疫「骨免疫学の20年 -骨と免疫の接点から骨免疫系の確立へ-」2020

    • Author(s)
      岡本一男、高柳広
    • Total Pages
      78
    • Publisher
      鳥居薬品(株)
    • Related Report
      2020 Annual Research Report
  • [Remarks] 東京大学大学院医学系研究科 免疫学 ホームページ

    • URL

      http://www.osteoimmunology.com/index.html

    • Related Report
      2021 Annual Research Report
  • [Remarks] 東京大学大学院医学系研究科 免疫学 研究室ホームページ

    • URL

      http://www.osteoimmunology.com

    • Related Report
      2020 Annual Research Report

URL: 

Published: 2020-07-30   Modified: 2024-03-26  

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