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The role of LILRB4 on MDSC-mediated immunosuppression in tumor environment

Research Project

Project/Area Number 19K16705
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 50010:Tumor biology-related
Research InstitutionTohoku University

Principal Investigator

SU Mei-Tzu  東北大学, 加齢医学研究所, 助教 (00812116)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
KeywordsMDSC / LILRB4 / gp49B / immunosuppression / metastasis / Immunosuppression / tumor metastasis / miRNA / immune checkpoint / immunotherapy / immune check point
Outline of Research at the Start

The myeloid-derived suppressor cell (MDSC) plays a critical role in cancer progression. Previous study reported the immunoglobulin-like receptor subfamily B member 4 (LILRB4) expressed on MDSCs correlates with survival in lung cancer patients. Herein, we aim to explore the mechanism of LILRB4 on MDSC-mediated tumor progression. This forefront study could benefit the development of a promising drug for MDSC targeting by blockade of LILRB4, and provide a new strategy for MDSC therapeutic targeting to overcome resistance to Immune checkpoint inhibitors (ICIs).

Outline of Final Research Achievements

Myeloid-derived suppressor cells (MDSCs) are involved in tumor-associated immunosuppression, and dominate tumor progression and metastasis. In this study, we report that the leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4, murine ortholog gp49B) orchestrates the polarization of MDSCs to exhibit pro-tumor phenotypes. Gp49B-/- MDSCs inhibited pro-tumor immune responses such as activation of Treg cells, promotion of cancer cell migration, and stimulation of tumor angiogenesis. Treatment of wild-type tumor-bearing mice with gp49B-/- M-MDSCs reduced cancer metastasis. Furthermore, gp49B knockout affected plasma exosome composition in terms of increased anti-tumor microRNAs expression. Collectively, our findings reveal that LILRB4/gp49B promotes MDSC-mediated tumor metastasis by regulating the M2-polarization of MDSCs and suppressing the secretion of miR-1 family miRNAs, which facilitate tumor migration and invasion.

Academic Significance and Societal Importance of the Research Achievements

Immune checkpoint inhibitors (ICIs) are used to enhance the antitumor immune response. Several patients do not respond to ICIs due to MDSC-mediated immune escape. Investigation of LILRB4 on how to contribute to MDSC-mediated immunosuppression could provide a new approach for ICI combination therapy.

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (12 results)

All 2022 2021 2020 2019

All Journal Article (3 results) (of which Peer Reviewed: 3 results,  Open Access: 3 results) Presentation (5 results) (of which Int'l Joint Research: 1 results,  Invited: 1 results) Patent(Industrial Property Rights) (3 results) Funded Workshop (1 results)

  • [Journal Article] LILRB4 promotes tumor metastasis by regulating MDSCs and inhibiting miR-1 family miRNAs2022

    • Author(s)
      Su Mei-Tzu、Kumata Sakiko、Endo Shota、Okada Yoshinori、Takai Toshiyuki
    • Journal Title

      OncoImmunology

      Volume: 11 Issue: 1

    • DOI

      10.1080/2162402x.2022.2060907

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Co-localization of Fibronectin Receptors LILRB4/gp49B and Integrin on Dendritic Cell Surface2022

    • Author(s)
      Takahashi Naoyuki, Itoi Sho, Su Mei-Tzu, Endo Shota, Takai Toshiyuki
    • Journal Title

      Tohoku J Expect Med.

      Volume: -

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Blockade of checkpoint ILT3/LILRB4/gp49B binding to fibronectin ameliorates autoimmune disease in BXSB/<i>Yaa</i> mice2021

    • Author(s)
      Su Mei-Tzu、Inui Masanori、Wong Yi Li、Takahashi Maika、Sugahara-Tobinai Akiko、Ono Karin、Miyamoto Shotaro、Murakami Keiichi、Itoh-Nakadai Ari、Kezuka Dai、Itoi So、Endo Shota、Hirayasu Kouyuki、Arase Hisashi、Takai Toshiyuki
    • Journal Title

      International Immunology

      Volume: 33 Issue: 8 Pages: 447-458

    • DOI

      10.1093/intimm/dxab028

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Blockade of checkpoint ILT3/LILRB4/gp49B binding to fibronectin ameliorates autoimmune disease in BXSB/Yaa mice2021

    • Author(s)
      Mei-Tzu Su, Masanori Inui, Shota Endo, Kouyuki Hirayasu, Hisashi Arase, Toshiyuki Takai
    • Organizer
      第50回日本免疫学会学術集会 (Web)
    • Related Report
      2021 Annual Research Report
  • [Presentation] The immune inhibitory receptor LILRB4/gp49B reduces anti-tumor exosomal miRNA levels in plasma through promoting MDSC-mediated immunosuppression2021

    • Author(s)
      Sakiko Kumata, Mei-Tzu Su, Shota Endo, Toshiyuki Takai
    • Organizer
      第50回日本免疫学会学術集会 (Web)
    • Related Report
      2021 Annual Research Report
  • [Presentation] Gp49B-fibronectin interaction negatively regulates osteoclastogenesis2021

    • Author(s)
      Dai Kezuka, Karin Ono, Mei-Tzu Su, Toshiyuki Takai
    • Organizer
      第50回日本免疫学会学術集会 (Web)
    • Related Report
      2021 Annual Research Report
  • [Presentation] Blockade of checkpoint ILT3/LILRB4/gp49B binding to fibronectin ameliorates autoimmune disease in BXSB/Yaa mice2021

    • Author(s)
      Mei-Tzu Su, Masanori Inui, Shota Endo, Toshiyuki Takai
    • Organizer
      Virtual IMMUNOLOGY 2021
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The immune inhibitory molecule LILRB4 regulates MDSC polarization to promote immunosuppression during tumor progression2021

    • Author(s)
      Mei-Tzu SU
    • Organizer
      9th Symposium of the Smart-Aging Research Center, Tohoku University
    • Related Report
      2020 Research-status Report
    • Invited
  • [Patent(Industrial Property Rights)] がん患者の予後を予測するためのバイオマーカー、がん患者の予後を予測するための方法、及び、がん患者の予後を予測するためのキット2021

    • Inventor(s)
      高井俊行、熊田早希子、岡田克典、SU MEI TZU 他
    • Industrial Property Rights Holder
      東北大学
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2021-119757
    • Filing Date
      2021
    • Related Report
      2021 Annual Research Report
  • [Patent(Industrial Property Rights)] 免疫チェックポイントB4-B4リガンド(フィブロネクチン)阻害剤2020

    • Inventor(s)
      高井俊行,乾 匡範,蘇 美慈,遠藤章太
    • Industrial Property Rights Holder
      高井俊行,乾 匡範,蘇 美慈,遠藤章太
    • Industrial Property Rights Type
      特許
    • Filing Date
      2020
    • Related Report
      2020 Research-status Report
  • [Patent(Industrial Property Rights)] Do not publish for confidentiality2019

    • Inventor(s)
      高井俊行、乾匡範、蘇美慈、遠藤章太
    • Industrial Property Rights Holder
      高井俊行、乾匡範、蘇美慈、遠藤章太
    • Industrial Property Rights Type
      特許
    • Filing Date
      2019
    • Related Report
      2019 Research-status Report
  • [Funded Workshop] Virtual IMMUNOLOGY2021 (www.immunology2021.org)2021

    • Related Report
      2021 Annual Research Report

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Published: 2019-04-18   Modified: 2023-01-30  

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