Investigation of mechanisms for the regulation of CD8 T cell exhaustion by type 2 diabetic drug, metfromin

• Project/Area Number: 16K18452
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor therapeutics
• Research Institution: Okayama University
• Principal Investigator: Eikawa Shingo 岡山大学, 医歯薬学総合研究科, 助教 (40635265)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: CD8 T細胞 / 代謝免疫 / メトホルミン / 好気的解糖 / グルコース / アミノ酸 / 2型糖尿病薬メトホルミン / 解糖系 / CD8T細胞 / エフェクター / がん免疫 / 代謝

Outline of Final Research Achievements

We previously argued that type 2 diabetic drug, metformin has an anti tumor effect mediated by the modulation of CD8 T cell function. In this study, we investigated further mechanisms of the effect on several mouse tumor implantation model. These results revealed the activation of AMPK in antigen-specific CD8 T cell by metformin is quite important for tumor regression. Metformin-induced AMPK activation led to enhance an aerobic glycolysis of CD8 T cell through cell membrane translocation of amino acid transpoter, LAT1. These data indicated CD8 T cell metabolism has an critical role for anti-tumor effect of metformin.

Research Products

• [Journal Article] Attenuation of CD4+CD25+regulatory T cells in the tumor microenvironment by metformin, a type 2 diabetes drug (2017)
  • Author(s): Kunisada Y, Eikawa S, Tomonobu N, Domae S, Uehara T, Hori S, Furusawa Y, Hase K, Sasaki A, Udono H.
  • Journal Title: EBioMedicine Volume: 25 Pages: 154-164
  • DOI: 10.1016/j.ebiom.2017.10.009
  • NAID: 120006767320
  • Peer Reviewed / Open Access
• [Journal Article] Study about the Efficacy of Metformin to Immune Function in Cancer Patients (2016)
  • Author(s): Watanabe M, Yamamoto H, Eikawa S, Shien K, Shien T, Soh J, Hotta K, Wada J, Hinotsu S, Fujiwara T, Kiura K, Doihara H, Miyoshi S, Udono H, Toyooka S
  • Journal Title: Acta Med Okayama Volume: 70 Pages: 327-330
  • NAID: 120005828926
  • Peer Reviewed / Int'l Joint Research
• [Presentation] CD8T細胞代謝制御によるがん免疫療法 (2017)
  • Author(s): 榮川伸吾
  • Organizer: 14回日本免疫治療学研究会学術集会
  • Place of Presentation: 東京大学伊藤国際学術研究センター B 2 F 学術集会会場
  • Year and Date: 2017-02-11
  • Invited
• [Presentation] がん微小環境におけるT細胞の代謝疲弊 (2017)
  • Author(s): 榮川伸吾、鵜殿平一郎
  • Organizer: 第27回日本サイトメトリー学会学術集会
  • Invited
• [Presentation] 胃癌患者末梢血中CD8 T細胞の多機能性と代謝の解析 (2017)
  • Author(s): 木村裕司、榮川伸吾、野島一郎、藤原俊義、鵜殿平一郎
  • Organizer: 第27回日本サイトメトリー学会学術集会
• [Presentation] 2型糖尿病患者CD8陽性T細胞におけるメトホルミンの影響 (2017)
  • Author(s): 野島一郎、榮川伸吾、友信奈保子、木村裕司、渡邉元嗣、鵜殿平一郎
  • Organizer: 第27回日本サイトメトリー学会学術集会
• [Presentation] 胃癌患者抹消血中CD8T細胞の多機能性と代謝の解析 (2017)
  • Author(s): 木村裕司、榮川伸吾、藤原俊義、鵜殿平一郎
  • Organizer: 第21回日本がん免疫学会総会
• [Presentation] 腫瘍微小環境の代謝改変によるがん免疫治療研究 (2017)
  • Author(s): 鵜殿平一郎、榮川伸吾、西田充香子
  • Organizer: 第5回がんと代謝研究会in札幌
• [Presentation] メトホルミンによる腫瘍浸潤制御性T細胞の抑制 (2017)
  • Author(s): 鵜殿平一郎、榮川伸吾、國定勇希
  • Organizer: 第38回日本炎症・再生医学会
• [Presentation] 腫瘍浸潤免疫細胞の代謝は抗腫瘍免疫応答を制御する (2017)
  • Author(s): 鵜殿平一郎、榮川伸吾、國定勇希、上原健敬、渡邉元嗣、木村裕司、佐々木朗、尾崎敏文、豊岡伸一、藤原俊義
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] メトホルミンはアミノ酸代謝を介してCD8T細胞の好気的解糖を促進する (2017)
  • Author(s): 榮川伸吾、友信奈保子、山下奈穂子、野島一郎、木村裕司、宮本学、福田真嗣、長谷耕二、鵜殿平一郎
  • Organizer: 第76回日本癌学会学術総会
  • Invited
• [Presentation] 胃癌患者における末梢血中CD8T細胞の多機能性と代謝の解析 (2017)
  • Author(s): 木村裕司、榮川伸吾、鵜殿平一郎、藤原俊義
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] 2型糖尿病薬メトホルミンによる腫瘍内制御性T細胞の機能抑制 (2017)
  • Author(s): 國定勇希、榮川伸吾、友信奈保子、銅前昇平、上原健敬、堀昇平、古澤之裕、長谷耕二、佐々木朗、鵜殿平一郎
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Analysis of multifunctionality and metabolism of peripheral blood CD8+ T cells in gastric cancer patients (2017)
  • Author(s): Yuji Kimura, Shingo Eikawa, Toshiyoshi Fujiwara, Heiichiro Udono
  • Organizer: 第5回国際サイトカイン・インターフェロン学会
  • Int'l Joint Research
• [Presentation] Metformin enhances aerobic glycolysis and amino acids metabolism in CD8+ T cells (2016)
  • Author(s): Shingo Eikawa, Nahoko Tomonobu, Fang He, Nahoko Yamashita, Mototsugu Watanabe, Yuji Kimura, Ichiro Nojima, Yuki Kunisada, Takenori Uehara, Chihiro Yamazaki, Shinji Fukuda, Koji Hase, Heiichiro Udono
  • Organizer: The 45th Annual Meeting of The Japanese Society for Immunology
  • Place of Presentation: 沖縄コンベンションセンター
  • Year and Date: 2016-12-07
  • Int'l Joint Research
• [Presentation] Metformin enhances aerobic glycolysis and amino acids metabolism in CD8+ T cells (2016)
  • Author(s): Shingo Eikawa, Nahoko Tomonobu, Fang He, Nahoko Yamashita, Mototsugu Watanabe, Yuji Kimura, Ichiro Nojima, Yuki Kunisada, Takenori Uehara, Chihiro Yamazaki, Shinji Fukuda, Koji Hase, Heiichiro Udono
  • Organizer: The 75th Annual Meeting of Japanese Cancer Association
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-10-08
• [Presentation] Metformin enhances aerobic glycolysis and amino acids metabolism in CD8+ T cells (2016)
  • Author(s): Shingo Eikawa, Nahoko Tomonobu, Fang He, Nahoko Yamashita, Mototsugu Watanabe, Yuji Kimura, Ichiro Nojima, Yuki Kunisada, Takenori Uehara, Chihiro Yamazaki, Shinji Fukuda, Koji Hase, Heiichiro Udono
  • Organizer: 第20回がん免疫学会総会
  • Place of Presentation: 大阪国際交流センタ
  • Year and Date: 2016-07-27
• [Book] がん免疫療法 (2017)
  • Author(s): 友信奈保子, 榮川伸吾, 鵜殿平一郎
  • Total Pages: 173
  • Publisher: 日本臨床
• [Book] 最新のがん免疫療法 (2016)
  • Author(s): 榮川伸吾、鵜殿平一郎
  • Total Pages: 176
  • Publisher: 医薬ジャーナル