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Dynamics of immune regulation in oral chronic inflammation and cancer, and their connection to systemic immunity

Research Project

Project/Area Number 18H04066
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Review Section Medium-sized Section 57:Oral science and related fields
Research InstitutionTokyo Medical and Dental University

Principal Investigator

Azuma Miyuki  東京医科歯科大学, 大学院医歯学総合研究科, 教授 (90255654)

Co-Investigator(Kenkyū-buntansha) 永井 重徳  東京医科歯科大学, 大学院医歯学総合研究科, 准教授 (50348801)
河野 洋平  東京医科歯科大学, 大学院医歯学総合研究科, 助教 (20401383)
大野 建州  東京医科歯科大学, 大学院医歯学総合研究科, 助教 (80435635)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥45,110,000 (Direct Cost: ¥34,700,000、Indirect Cost: ¥10,410,000)
Fiscal Year 2020: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000)
Fiscal Year 2019: ¥10,010,000 (Direct Cost: ¥7,700,000、Indirect Cost: ¥2,310,000)
Fiscal Year 2018: ¥26,000,000 (Direct Cost: ¥20,000,000、Indirect Cost: ¥6,000,000)
Keywords免疫制御 / 口腔粘膜 / 口腔癌 / 免疫チェックポイント分子 / 制御細胞 / 慢性炎症 / 免疫抑制御 / T細胞
Outline of Final Research Achievements

To clarify “negative immune responses” in the state of chronic clinical condition, we investigated regulatory cells in the chronic mucosal lesion and squamous cell carcinoma in the oral cavity. We observed two unique features of regulatory cells; Foxp3+ resident memory regulatory T cells in the buccal mucosa after repeated antigen painting, and IL-10-expressing CD206+ macrophages, which negatively regulate antigen-presenting capacity of nearby dendritic cells in the sublingual mucosa after repeated antigen painting. The studies using PD-1 immune checkpoint inhibitor-resistant squamous carcinoma cell models revealed that differences of myeloid cells in the tumor microenvironment (TME) affected the efficacies of additional immune therapy. Furthermore, our results demonstrated that immune profiles in the TME between tongue and skin inoculation were quite different.

Academic Significance and Societal Importance of the Research Achievements

口腔粘膜慢性炎症における制御細胞および制御分子を標的とした慢性炎症制御の可能性が示された。本研究を発展させ、口腔癌におけるがん微少環境の免疫プロファイリングを明確にし、予後評価の指標となる免疫スコア(バイオマーカー)を同定すれば、口腔癌治療の指針に組み入れることができ、再発・転移症例に減少に繋がり、その社会的意義は大きい。また、免疫チェックポイント阻害剤で効果が得られない症例把握も可能となる。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • Research Products

    (33 results)

All 2021 2020 2019 2018

All Journal Article (10 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 10 results,  Open Access: 8 results) Presentation (22 results) (of which Int'l Joint Research: 6 results) Book (1 results)

  • [Journal Article] Polymorphonuclear myeloid-derived cells that contribute to the immune paralysis are generated in the early phase of sepsis vis the PD-1/PD-L1 pathway2021

    • Author(s)
      Ao Xiang、Yang Yue、Okiji Takashi、Azuma Miyuki、Nagai Shigenori
    • Journal Title

      Infection and Immunity, Online ahead of print.

      Volume: - Issue: 6

    • DOI

      10.1128/iai.00771-20

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] PD-L2 preferentially forms coinhibitory microclusters with both PD-1 and TCRs and recruiting the phosphatase SHP2 suppress TCR signaling2021

    • Author(s)
      Takehara T, Wakamatsu E, Machiyam H, Nishi W, Emoto K, Azuma M, Soejima K, Fukunaga K, Yokosuka T.
    • Journal Title

      Communications Biology, in press

      Volume: -

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Blockade Of PD-1 attenuated postsepsis aspergillosis via the activation of IFN-γ and the dampening of IL-10.2020

    • Author(s)
      Vu CTB, Thammahong A, Yagita H, Azuma M, Hiyanyakarn N, Ritprajak P, Leelahavanichkul A.
    • Journal Title

      SHOCK

      Volume: 53 Issue: 4 Pages: 514-524

    • DOI

      10.1097/shk.0000000000001392

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Tolerogenic properties of CD206+ macrophages appeared in the sublingual mucosa after repeated antigen-painting.2020

    • Author(s)
      Yang Y, Nagai S, Kang S, Xia Y, Kawano Y, Miyake K, Karasuyama H, Azuma M.
    • Journal Title

      International Immunology

      Volume: - Issue: 8 Pages: 509-518

    • DOI

      10.1093/intimm/dxaa014

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Orthotopic tongue squamous cell carcinoma (SCC) model exhibiting a different tumor-infiltrating T-cell status with margin-restricted CD8+ T cells and regulatory T cell-dominance, compared to skin SCC.2020

    • Author(s)
      Kashima Y, Nishii N, Tachinami H, Furusawa E, Nagai S, Harada H, Azuma M.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 20 Issue: 1 Pages: 218-224

    • DOI

      10.1016/j.bbrc.2020.03.022

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Critical role of PD-L1 expression on non-tumor cells rather than on tumor cells for effective anti-PD-L1 immunotherapy in a transplantable mouse hematopoietic tumor model2020

    • Author(s)
      Rodriguez-Barbosa Jose-Ignacio、Azuma Miyuki、Zelinskyy Gennadiy、Perez-Simon Jose-Antonio、del Rio Maria-Luisa
    • Journal Title

      Cancer Immunology, Immunotherapy

      Volume: 69 Issue: 6 Pages: 1001-1014

    • DOI

      10.1007/s00262-020-02520-z

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Differences of tumor-recruiting myeloid cells in murine squamous cell carcinoma influence the efficacy of immunotherapy combined with a TLR7 agonist and PD-L1 blockade2019

    • Author(s)
      Tachinami Hidetake、Nishii Naoto、Xia Yulong、Kashima Yoshihisa、Ohno Tatsukuni、Nagai Shigenori、Li Lixin、Lau Walter、Tomihara Kei、Noguchi Makoto、Azuma Miyuki
    • Journal Title

      Oral Oncology

      Volume: 91 Pages: 21-28

    • DOI

      10.1016/j.oraloncology.2019.02.014

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Silencing of PD-L2/B7-DC by Topical Application of Small Interfering RNA Inhibits Elicitation of Contact Hypersensitivity2019

    • Author(s)
      Furusawa Emi、Ohno Tatsukuni、Nagai Shigenori、Noda Taisei、Komiyama Takuya、Kobayashi Katsunori、Hamomato Hidetoshi、Miyashin Michiyo、Yokozeki Hiroo、Azuma Miyuki
    • Journal Title

      Journal of Investigative Dermatology

      Volume: - Issue: 10 Pages: 2164-2173

    • DOI

      10.1016/j.jid.2019.02.037

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Endogenous IL-33 exerts CD8+ T cell antitumor responses overcoming pro-tumor effects by regulatory T cells in a colon carcinoma model.2019

    • Author(s)
      Xia Y, Ohno T, Nishii N, Bhingare A, Tachinami H, Kashima Y, Nagai S, Saito H, Nakae S, Azuma M.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 2019 Issue: 2 Pages: 331-336

    • DOI

      10.1016/j.bbrc.2019.08.058

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] VISTA expressed in tumour cells regulates T cell function2018

    • Author(s)
      Mulati Kumuluzi、Hamanishi Junzo、Matsumura Noriomi、Chamoto Kenji、Mise Nathan、Abiko Kaoru、Baba Tsukasa、Yamaguchi Ken、Horikawa Naoki、Murakami Ryusuke、Taki Mana、Budiman Kharma、Zeng Xiang、Hosoe Yuko、Azuma Miyuki、Konishi Ikuo、Mandai Masaki
    • Journal Title

      British Journal of Cancer

      Volume: 120 Issue: 1 Pages: 115-127

    • DOI

      10.1038/s41416-018-0313-5

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] マルチプレックス免疫組織染色による舌扁平上皮癌の免疫プロファイリング解析2021

    • Author(s)
      Pissacha Daroonpan, 加島 義久、濱垣 美和子、西井 直人、津島 文彦、原田 浩之、池田 通、東 みゆき.
    • Organizer
      第75回日本口腔科学会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Overexpression of gingiva-associated PD-L1 inhibits gingival/periodontal inflammation2020

    • Author(s)
      Wongtim Keeratika、池田 恵莉、大野 建州、永井 重徳、奥原 滋、呉 圭哲、東 みゆき.
    • Organizer
      第74回日本口腔科学会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Gingival keratinocyte-associated immune checkpoint PD-L1 inhibits periodontal inflammation2020

    • Author(s)
      Wongtim Keeratika、永井 重徳、奥原 滋、東 みゆき
    • Organizer
      第62回歯科基礎医学会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Binding and functional properties of VSIG4(V-set and Ig domain containing 4)-Ig fusion protein.2020

    • Author(s)
      Widyagarini Amrita、永井 重徳、東 みゆき.
    • Organizer
      第62回歯科基礎医学会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 境界部に限局したCD8+T細胞と制御性T細胞の浸潤を認める同所性マウス舌扁平上皮癌モデル2020

    • Author(s)
      加島 義久、西井 直人、立浪 秀剛、永井 重徳、原田 浩之、東 みゆき.
    • Organizer
      第79回日本癌学会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Silencing of PD-L2/B7-DC by topical application of small iInterfering RNA inhibits elicitation of contact hypersensitivity.2019

    • Author(s)
      Furusawa E, Ohno T, Nagai S, Noda T, Komiyama T, Kobayashi K, Hamamoto H, Miyashin M, Yokozeki H, Azuma M.
    • Organizer
      AAI 2019 (The American Association of Immunologists, Immunology2019)
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Differences of tumor-recruiting myeloid cells in murine squamous cell carcinoma influence the efficacy of immunotherapy combined with a TLR7 agonist and PD-L1 blockade.2019

    • Author(s)
      Azuma M, Tachinami H, Nishii N, Xia Y, Kashima Y, Nagai S, Li L, Tomihara K, Noguchi M.
    • Organizer
      17th IUIS 2019 (International Congress of Immunology)
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Silencing of PD-L2 by topical application of small interfering RNA inhibits elicitation of contact hypersensitivity.2019

    • Author(s)
      Azuma M, Furusawa E, Nagai S, Yokozeki H.
    • Organizer
      17th IUIS 2019 (International Congress of Immunology)
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Repeated antigen painting induces tolerogenic cells in sublingual mucosa.2019

    • Author(s)
      Yang Y, Nagai S, Azuma M.
    • Organizer
      17th IUIS 2019 (International Congress of Immunology)
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] マウス舌癌モデルの樹立と免疫組織学的解析.2019

    • Author(s)
      加島 義久、立浪 秀剛、東 みゆき、原田 浩之.
    • Organizer
      第73回日本口腔科学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 腫瘍に集積するミエロイド系細胞の違いはPD-L1阻害剤との併用免疫療法効果に影響を与える.2019

    • Author(s)
      立浪 秀剛、西井 直人、加島 義久、冨原 圭、野口 誠、東 みゆき.
    • Organizer
      第73回日本口腔科学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 慢性口腔粘膜炎症におけるレジデントメモリーT細胞の性状と機能.2019

    • Author(s)
      古澤 慧美、宮新 美智代、東 みゆき.
    • Organizer
      第84回口腔病学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Identification of a unique macrophage subset induced by repeated antigen painting in sublingual mucosa to regulate T cell tolerance.2019

    • Author(s)
      Yang Y, Nagai S, Azuma M.
    • Organizer
      第48回日本免疫学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] One of PD-1 ligand、PD-L2 induced on Langerhans cells augments cutaneous T cell-mediated immune responses.2019

    • Author(s)
      Furusawa E, Ohno T, Nagai S, Komiyama T, Kobayashi K, Hamamoto H, Miyashin M, Yokozeki H, Azuma M.
    • Organizer
      第48回日本免疫学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 2つのマウス扁平上皮癌モデルの癌微小環境におけるミエロイド系細胞の相違とTLR7アゴニストの投与効果2018

    • Author(s)
      立浪 秀剛、西井 直人、加島 義久、加藤 寛史、冨原 圭、野口 誠、東 みゆき
    • Organizer
      第72回日本口腔科学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Topical application of B7-DC/PD-L2 siRNA inhibits contact hypersensitivity2018

    • Author(s)
      Furusawa E, Ohno T, Miyashin M, Azuma M
    • Organizer
      15th International Symposium on Dendritic Cells
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Systemic administration of a TLR7 agonist attenuates regulatory T cells by dendritic cell modification and overcomes resistance to PD-L1 blockade therapy2018

    • Author(s)
      Nishii N, Tachinami H, Kondo Y, Xia Y, Kashima Y, Ohno T, Nagai S, Li L, Lau W, Harada H, Azuma M
    • Organizer
      15th International Symposium on Dendritic Cells
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Immunosuppressive status of CD206hl cells appeared in sublingual mucosa2018

    • Author(s)
      Yang Yue、永井 重徳、東 みゆき
    • Organizer
      第60回歯科基礎医学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 抗腫瘍応答における内因性および腫瘍内投与IL-33の機能評価2018

    • Author(s)
      夏 玉龍、西井 直人、永井 重徳、東 みゆき、大野 建州
    • Organizer
      第77回日本癌学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 2つのマウス扁平上皮癌モデルの癌微小環境におけるミエロイド系細胞の相違とTLR7アゴニストの投与効果2018

    • Author(s)
      立浪 秀剛、西井 直人、永井 重徳、加島 義久、冨原 圭、野口 誠、東 みゆき
    • Organizer
      第77回日本癌学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Silencing effects of B7-DC in cutaneous DCs on allergic skin diseases2018

    • Author(s)
      Furusawa E, Noda T, Komiyama T, Ohno T, Yokozeki H, Kobayashi K, Hamamoto H, Miyashin M, Azuma M
    • Organizer
      第47回日本免疫学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Involvement of CD206+ cells in oral mucosal tolerance2018

    • Author(s)
      Yang Y, Nagai S, Azuma M
    • Organizer
      第47回日本免疫学会
    • Related Report
      2018 Annual Research Report
  • [Book] Co-signal Molecules in T Cell Activation2019

    • Author(s)
      Miyuki Azuma, Hideo Yagita
    • Total Pages
      326
    • Publisher
      Springer
    • ISBN
      9789813297166
    • Related Report
      2019 Annual Research Report

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Published: 2018-04-23   Modified: 2022-01-27  

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