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Reversion of exhausted T cells in tumor microenvironment

Research Project

Project/Area Number 26670237
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeMulti-year Fund
Research Field Immunology
Research InstitutionOkayama University

Principal Investigator

Udono Heiichiro  岡山大学, 医歯(薬)学総合研究科, 教授 (50260659)

Project Period (FY) 2014-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywords免疫疲弊 / CD8T細胞 / 腫瘍微小環境 / メトホルミン / エフェクター・メモリー / AMPK / アポトーシス / サイトカイン
Outline of Final Research Achievements

Elevation of glycolysis in CD8 tumor infiltration lymphocyte (CD8TIL) was found by metformin (Met) administration. Also, mature CD8T cells differentiated from naive CD8T cells by in vitro TCR stimulation revealed enhanced glycolysis as well as oxidative phosphorylation by Met-treatment. Intestinal micro flora was not altered by Met. Significant reduction of Treg in tumors was also observed by Met. Inducible Treg (iTreg) differentiated from naive CD4T cells by TCR stimulation and TGFbeta was reduced in number and suppressive function by Met-treatment. Furthermore, reduction of MDSC in number, especially, G-MDSC rather than M-MDSC, was prominent in tumor tissue by Met. Also, increase of M1/M2 macrophage ration was observed by Met. It is clear that Met-administration dramatically changes tumor microenvironment towards favorable state for anti-tumor immunity.

Report

(3 results)
  • 2015 Annual Research Report   Final Research Report ( PDF )
  • 2014 Research-status Report
  • Research Products

    (27 results)

All 2016 2015 2014

All Journal Article (6 results) (of which Peer Reviewed: 6 results,  Open Access: 6 results,  Acknowledgement Compliant: 3 results) Presentation (18 results) (of which Int'l Joint Research: 1 results,  Invited: 16 results) Book (1 results) Patent(Industrial Property Rights) (2 results) (of which Overseas: 1 results)

  • [Journal Article] The induction of antigen-specific CTL by in situ Ad-REIC gene therapy.2016

    • Author(s)
      Ariyoshi Y, Watanabe M, Eikawa S, Yamazaki C, Sadahira T, Hirata T, Araki M, Ebara S, Nasu Y, Udono H, Kumon H.
    • Journal Title

      Gene Ther.

      Volume: gt.2016.7 Issue: 5 Pages: 408-414

    • DOI

      10.1038/gt.2016.7

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Phase Ia Study of FoxP3+ CD4 Treg Depletion by Infusion of a Humanized Anti-CCR4 Antibody, KW-0761, in Cancer Patients.2015

    • Author(s)
      2.Kurose K, Ohue Y, Wada H, Iida S, Ishida T, Kojima T, Doi T, Suzuki S, Isobe M, Funakoshi T, Kakimi K, Nishikawa H, Udono H, Oka M, Ueda R, Nakayama E.
    • Journal Title

      Clin Cancer Res.

      Volume: 21 Issue: 19 Pages: 4327-36

    • DOI

      10.1158/1078-0432.ccr-15-0357

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Detection and Tracking of NY-ESO-1-Specific CD8+ T Cells by High-Throughput T Cell Receptor β (TCRB) Gene Rearrangements Sequencing in a Peptide-Vaccinated Patient.2015

    • Author(s)
      Miyai M, Eikawa S, Hosoi A, Iino T, Matsushita H, Isobe M, Uenaka A, Udono H, Nakajima J, Nakayama E, Kakimi K.
    • Journal Title

      PLoS One

      Volume: 10(8) Issue: 8 Pages: e0136086-e0136086

    • DOI

      10.1371/journal.pone.0136086

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Immunotherapy for Bone and Soft Tissue Sarcomas2015

    • Author(s)
      Uehara T, Fujiwara T, Takeda K, Kunisada T, Ozaki T, Udono H.
    • Journal Title

      Biomed Res Int

      Volume: 69 Pages: 820813-820813

    • DOI

      10.1155/2015/820813

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Immune-mediated anti-tumor effect by type 2 diabetes drug, metformin.2015

    • Author(s)
      Eikawa S, Nishida M, Mizukami S, Yamazaki C, Nakayama E and Udono H.
    • Journal Title

      Pros Natl Acd Sci USA

      Volume: 112 (6) Issue: 6 Pages: 1809-1814

    • DOI

      10.1073/pnas.1417636112

    • Related Report
      2015 Annual Research Report 2014 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] HSP90α plays an important role in piRNA biogenesis and retrotransposon repression in mouse2014

    • Author(s)
      Ichiyanagi, T., Ichiyanagi, K., Ogawa, A., Kuramochi-Miyagawa, S., Nakano, T., Chuma, S., Sasaki, H.
    • Journal Title

      Nucleic Acids Res

      Volume: 42 Issue: 19 Pages: 11903-11

    • DOI

      10.1093/nar/gku881

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 2型糖尿病治療薬メトホルミンの腫瘍微小環境に与える影響2016

    • Author(s)
      鵜殿平一郎
    • Organizer
      北海道大博大学大学院セミナー
    • Place of Presentation
      北海道大学遺伝子病研究所(北海道)
    • Year and Date
      2016-03-15
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] 2型糖尿病治療薬メトホルミンの腫瘍微小環境に与える影響2016

    • Author(s)
      鵜殿平一郎
    • Organizer
      がん免疫療法最前線 日本が発するヒトがん免疫制御の新世界基準
    • Place of Presentation
      Sola City Conference Center 東京(東京)
    • Year and Date
      2016-03-14
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] がん免疫研究の最前線     免疫疲弊解除研究2016

    • Author(s)
      鵜殿平一郎
    • Organizer
      山田養蜂場みつばち研究助成金 第7回成果発表会
    • Place of Presentation
      岡山県津山市(岡山)
    • Year and Date
      2016-03-04
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] 2型糖尿病治療薬メトホルミンの腫瘍微小環境に与える影響2016

    • Author(s)
      鵜殿平一郎
    • Organizer
      長崎大学大学院セミナー
    • Place of Presentation
      長崎大学ポンぺ会館(長崎)
    • Year and Date
      2016-02-25
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] 変貌するがん免疫治療2016

    • Author(s)
      鵜殿平一郎
    • Organizer
      熊本呼吸器フォーラム分科会
    • Place of Presentation
      ホテルニューオータニ熊本(熊本)
    • Year and Date
      2016-02-18
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] Metformin-induced reversion of exhausted CD8T cells in tumor microenvironment2016

    • Author(s)
      Heiichiro Udono
    • Organizer
      Nagoya International Cancer Treatment Symposium
    • Place of Presentation
      Aichi Cancer Center(愛知)
    • Year and Date
      2016-02-13
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 腫瘍局所浸潤CD8T細胞の免疫疲弊解除と解糖系2016

    • Author(s)
      鵜殿平一郎
    • Organizer
      メトホルミンセミナー
    • Place of Presentation
      金沢大学付属病院(金沢)
    • Year and Date
      2016-01-25
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] メトホルミンによる腫瘍浸潤T細胞の疲弊解除2015

    • Author(s)
      鵜殿平一郎
    • Organizer
      第5回Metabolic Scientific Forum
    • Place of Presentation
      ステーションコンファレンス東京(東京)
    • Year and Date
      2015-12-19
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] Anti-cancer immunity elicited by type 2 diabetes drug metformin, is mediated by reversion of exhausted CD8T cells within tumor tissues.2015

    • Author(s)
      鵜殿平一郎
    • Organizer
      The 40th Annual Meeting of the Japanese Society for Investigative Dermatology
    • Place of Presentation
      Okayama Convention Center(岡山)
    • Year and Date
      2015-12-11
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] メトホルミンは腫瘍局所浸潤CD8T細胞の解糖を促進する2015

    • Author(s)
      鵜殿平一郎
    • Organizer
      第88回日本生化学会
    • Place of Presentation
      神戸ポートアイランド(兵庫)
    • Year and Date
      2015-12-01
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] メトホルミン誘導性の免疫疲弊解除によるがん免疫治療2015

    • Author(s)
      鵜殿平一郎
    • Organizer
      BioJapan 2015
    • Place of Presentation
      パシフィコ横浜(神奈川)
    • Year and Date
      2015-10-15
    • Related Report
      2015 Annual Research Report
  • [Presentation] 変貌するがん免疫治療 -がんは免疫の力で治せるのか?-2015

    • Author(s)
      鵜殿平一郎
    • Organizer
      第34回鹿児島呼吸器内科セミナー
    • Place of Presentation
      鹿児島大学共通教育棟(鹿児島)
    • Year and Date
      2015-06-23
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] 2型糖尿病治療薬メトホルミンによる免疫疲弊解除2015

    • Author(s)
      鵜殿平一郎
    • Organizer
      第68回日本酸化ストレス学会学術集会
    • Place of Presentation
      かごしま県民交流センター(鹿児島)
    • Year and Date
      2015-06-12
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] 腫瘍局所免疫疲弊解除によるがん免疫治療2015

    • Author(s)
      鵜殿平一郎
    • Organizer
      第14回国際バイオテクノロジー展
    • Place of Presentation
      東京ビッグサイト(東京)
    • Year and Date
      2015-05-15
    • Related Report
      2015 Annual Research Report
  • [Presentation] メトホルミンによる腫瘍局所の免疫疲弊解除2015

    • Author(s)
      鵜殿平一郎
    • Organizer
      第12回日本免疫治療学研究会学術集会
    • Place of Presentation
      東京ガーデンパレス
    • Year and Date
      2015-02-28
    • Related Report
      2014 Research-status Report
    • Invited
  • [Presentation] エネルギーセンサーを介したストレス応答と腫瘍免疫の関わり2014

    • Author(s)
      鵜殿平一郎
    • Organizer
      第9回臨床ストレス応答学会
    • Place of Presentation
      岡山大学鹿田キャンパス
    • Year and Date
      2014-11-01 – 2014-11-02
    • Related Report
      2014 Research-status Report
    • Invited
  • [Presentation] メトホルミンによる腫瘍局所の免疫疲弊解除2014

    • Author(s)
      鵜殿平一郎、榮川伸吾
    • Organizer
      第87回日本生化学会大会
    • Place of Presentation
      京都国際会館
    • Year and Date
      2014-10-17
    • Related Report
      2014 Research-status Report
    • Invited
  • [Presentation] Metformin-induced reversion of exhausted CD8T cells in tumor microenvironment.2014

    • Author(s)
      Udono H, Nishida M, Eikawa S.
    • Organizer
      73rd Annual Meeting of the Japanese Cancer Association
    • Place of Presentation
      パシフィコ横浜
    • Year and Date
      2014-09-25 – 2014-09-27
    • Related Report
      2014 Research-status Report
    • Invited
  • [Book] T細胞の免疫疲弊と免疫チェックポイント分子2015

    • Author(s)
      榮川伸吾、鵜殿平一郎
    • Publisher
      最新医学(70巻3号)
    • Related Report
      2014 Research-status Report
  • [Patent(Industrial Property Rights)] 免疫細胞の機能増強方法及び免疫細胞の多機能性評価方法2015

    • Inventor(s)
      鵜殿平一郎、榮川伸吾、豊岡伸一
    • Industrial Property Rights Holder
      国立大学法人 岡山大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2015-08-17
    • Related Report
      2015 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] 免疫評価方法とその評価された免疫活性化剤2014

    • Inventor(s)
      鵜殿平一郎、榮川伸吾、 豊岡伸一
    • Industrial Property Rights Holder
      鵜殿平一郎、榮川伸吾、 豊岡伸一
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2014-166593
    • Filing Date
      2014-08-19
    • Related Report
      2014 Research-status Report

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Published: 2014-04-04   Modified: 2017-05-10  

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