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Elucidation of the role of cholesterol sulfate in tumor immune privilege formation and its application for drug development

Research Project

Project/Area Number 21H02430
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 43030:Functional biochemistry-related
Research InstitutionKyushu University

Principal Investigator

Uruno Takehito  九州大学, 生体防御医学研究所, 准教授 (80532093)

Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2023: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2022: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
Fiscal Year 2021: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
Keywords腫瘍免疫 / メタボライト / コレステロール硫酸 / 免疫回避 / SULT / 硫酸化 / 治療抵抗性 / コレステロール / 創薬 / がん免疫療法 / SULT2B1b / DOCK2 / 腫瘍微小環境 / 免疫特権
Outline of Research at the Start

硫酸化コレステロール(Cholesterol sulfate: CS)はRac活性化因子DOCK2の内因性阻害因子として働き、免疫細胞の遊走をブロックすることで眼の組織特異的免疫回避(免疫特権)に寄与している。CSを産生する酵素SULT2B1bは様々ながん種で高発現していることから、CSは腫瘍の免疫回避にも寄与する可能性が高い。本研究は、CSを介した腫瘍免疫特権の全容を解明すると共に、新たな抗がん剤シードとしてCS産生阻害剤を開発することを目的とする。本研究の成果は、腫瘍免疫をターゲットにした新しい治療薬の創出につながることが期待される。

Outline of Final Research Achievements

This study identified cholesterol sulfate (CS) and its producing enzyme SULT2B1 as a novel tumor immune evasion mechanism that contributes to resistance to cancer immunotherapy. The study demonstrates that CS released from SULT2B1-expressing cancer cells forms an immunosuppressive chemical barrier (immune privilege) in the tumor microenvironment that prevents T cell infiltration into the tumor and thus contributes to immunotherapy resistance. In the human clinical database, SULT2B1 gene expression is highly correlated with poor prognosis and immunosuppression in multiple cancer types. Independent screening identified a small molecule inhibitor that suppresses CS production in SULT2B1-expressing cancer cells and demonstrated that the inhibitor can be used to diminish the immunotherapy resistance and enhance the efficacy of immune checkpoint blockade and anti-tumor T cell transfer.

Academic Significance and Societal Importance of the Research Achievements

本研究は、がん細胞によって産生されるコレステロール代謝産物が腫瘍微小環境において免疫抑制性の化学的バリア(免疫特権)を形成し、がんの免疫逃避に働くことを初めて明らかにした。独自のスクリーニングで見出したCS産生酵素SULT2B1の阻害剤は、がん免疫を賦活化し免疫チェックポイント阻害や抗原特異的T細胞療法に対する抵抗性を解除した。臨床データ解析によって複数のがん種ではSULT2B1発現と患者の予後不良や免疫機能低下の間に高い相関が示された。すなわち、本研究によって新たながんの免疫逃避機構の一つが解明され、がん免疫療法に対する抵抗性を解除する手法の一つとしてSULT2B1阻害の有用性が示された。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • Research Products

    (17 results)

All 2024 2023 2022 2021 Other

All Journal Article (7 results) (of which Peer Reviewed: 6 results,  Open Access: 6 results) Presentation (7 results) (of which Int'l Joint Research: 1 results,  Invited: 1 results) Remarks (1 results) Patent(Industrial Property Rights) (2 results) (of which Overseas: 1 results)

  • [Journal Article] Cholesterol sulfate limits neutrophil recruitment and gut inflammation during mucosal injury.2023

    • Author(s)
      Morino K#, Kunimura K#*, Sugiura Y, Izumi Y, Matsubara K, Akiyoshi S, Maeda R, Hirotani K, Sakata D, Mizuno S, Takahashi S, Bamba T, Uruno T, Fukui Y*.
    • Journal Title

      Frontiers in Immunology

      Volume: 14 Pages: 1131146-1131146

    • DOI

      10.3389/fimmu.2023.1131146

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] DOCK2 regulates MRGPRX2/B2-mediated mast cell degranulation and drug-induced anaphylaxis2023

    • Author(s)
      Kunimura Kazufumi、Akiyoshi Sayaka、Uruno Takehito、Matsubara Keisuke、Sakata Daiji、Morino Kenji、Hirotani Kenichiro、Fukui Yoshinori
    • Journal Title

      Journal of Allergy and Clinical Immunology

      Volume: - Issue: 6 Pages: 0-0

    • DOI

      10.1016/j.jaci.2023.01.029

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Pharmacological intervention of cholesterol sulfate-mediated T cell exclusion promotes antitumor immunity.2022

    • Author(s)
      Tatsuguchi T#, Uruno T#*, Sugiura Y, Oisaki K, Takaya D, Sakata D, Izumi Y, Togo T, Hattori Y, Kunimura K, Sakurai T, Honma T, Bamba T, Nakamura M, Kanai M, Suematsu M, Fukui Y*.
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 609 Pages: 183-188

    • DOI

      10.1016/j.bbrc.2022.04.035

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of a functional DOCK8 gene polymorphism associated with atopic dermatitis2022

    • Author(s)
      Kunimura Kazufumi、Yamamura Kazuhiko、Nakahara Takeshi、Kido‐Nakahara Makiko、Uruno Takehito、Fukui Yoshinori
    • Journal Title

      Allergy

      Volume: 77 Issue: 12 Pages: 3670-3672

    • DOI

      10.1111/all.15429

    • Related Report
      2022 Annual Research Report
  • [Journal Article] Cancer-derived cholesterol sulfate is a key mediator to prevent tumor infiltration by effector T cells2022

    • Author(s)
      Tatsuguchi T., Uruno T., Sugiura Y., Sakata D., Izumi Y., Sakurai T., Hattori Y., Oki E., Kubota N., Nishimoto K., Oyama M., Kunimura K., Ohki T., Bamba T., Tahara H., Sakamoto M., Nakamura M., Suematsu M., Fukui Y.
    • Journal Title

      Int. Immunol.

      Volume: - Issue: 5 Pages: 277-289

    • DOI

      10.1093/intimm/dxac002

    • Related Report
      2022 Annual Research Report 2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Targeted inhibition of EPAS1-driven IL-31 production by a small-molecule compound.2021

    • Author(s)
      Kamikaseda Y, Uruno T, Kunimura K, Harada A, Saiki K, Oisaki K, Sakata D, Nakahara T, Kido-Nakahara M, Kanai M, Nakamura S, Ohkawa Y, Furue M, Fukui Y.
    • Journal Title

      J Allergy Clin Immunol.

      Volume: 148 Issue: 2 Pages: 633-638

    • DOI

      10.1016/j.jaci.2021.03.029

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 2.論文標題 DOCK8 deficiency causes a skewing to type 2 immunity in the gut with expansion of group 2 innate lymphoid cells.2021

    • Author(s)
      Matsubara K, Kunimura K, Yamane N, Aihara R, Sakurai T, Sakata D, Uruno T, Fukui Y
    • Journal Title

      Biochem. Biophys. Res. Commun.

      Volume: 559 Pages: 135-140

    • DOI

      10.1016/j.bbrc.2021.04.094

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] ホスファチジン酸産生酵素PLD1は好中球細胞外トラップの形成に必須である2024

    • Author(s)
      宇留野武人、相原良亮
    • Organizer
      第101回日本生理学会大会
    • Related Report
      2023 Annual Research Report
  • [Presentation] がん免疫療法に対する抵抗性を付与する腫瘍メタボライト2023

    • Author(s)
      宇留野武人、竜口崇明、杉浦悠毅、福井宣規
    • Organizer
      第27回日本がん免疫学会総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] A tumor metabolite impacting immunotherapy efficacy: Cholesterol sulfate regulates tumor-immune interactions2023

    • Author(s)
      Takehito Uruno
    • Organizer
      Keystone Symposia on Cancer Immunotherapy: Mechanisms of Response versus Resistance
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] マウスハーダー腺の加齢に伴うトランスクリプトーム・リピドーム変化2023

    • Author(s)
      宇留野武人、高橋政友
    • Organizer
      日本生理学会 第100回記念大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] コレステロール硫酸を介した腫瘍の免疫回避と創薬応用2022

    • Author(s)
      宇留野武人
    • Organizer
      第95回日本生化学大会 シンポジウム
    • Related Report
      2022 Annual Research Report
  • [Presentation] コレステロール硫酸は白血球の遊走制御を介して眼の免疫特権環境の形成に寄与する2022

    • Author(s)
      國村和史、宇留野武人、杉浦悠毅、福井宣規
    • Organizer
      第95回日本生化学大会 シンポジウム
    • Related Report
      2022 Annual Research Report
  • [Presentation] RAS変異を有する難治性がんの新規分子標的治療薬の開発2021

    • Author(s)
      宇留野武人、坂田大治、福井宣規、生長幸之助
    • Organizer
      第94回日本生化学会大会シンポジウム講演、京都, 2021
    • Related Report
      2021 Annual Research Report
  • [Remarks] 研究機関 研究者情報

    • URL

      https://hyoka.ofc.kyushu-u.ac.jp/search/details/K004217/index.html

    • Related Report
      2022 Annual Research Report
  • [Patent(Industrial Property Rights)] IL-31産生抑制剤、及びそれを含有する医薬組成物2022

    • Inventor(s)
      福井宣規、宇留野武人、他
    • Industrial Property Rights Holder
      福井宣規、宇留野武人、他
    • Industrial Property Rights Type
      特許
    • Filing Date
      2022
    • Related Report
      2021 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] SULT2B1b阻害剤、CS生成阻害剤、及び抗がん免疫増強作用を有する医薬組成物2021

    • Inventor(s)
      福井宣規、宇留野武人、他
    • Industrial Property Rights Holder
      福井宣規、宇留野武人、他
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2021-173456
    • Filing Date
      2021
    • Related Report
      2021 Annual Research Report

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Published: 2021-04-28   Modified: 2025-01-30  

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