Updated on 2025/04/17

写真a

 
Tokumasu Miho
 
Organization
Faculty of Medicine, Dentistry and Pharmaceutical Sciences Assistant Professor
Position
Assistant Professor
External link

Research Areas

  • Life Science / Molecular biology

  • Life Science / Immunology

 

Papers

  • Tob negatively regulates NF-κB activation in breast cancer through its association with the TNF receptor complex. Reviewed International journal

    Miho Tokumasu, Atsuko Sato, Taku Ito-Kureha, Mizuki Yamamoto, Nao Ohmine, Kentaro Semba, Jun-Ichiro Inoue, Tadashi Yamamoto

    Cancer gene therapy   2025.4

     More details

    Authorship:Lead author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    NF-κB mediates transcriptional regulation crucial to many biological functions, and elevated NF-κB activity leads to autoimmune and inflammatory diseases, as well as cancer. Since highly aggressive breast cancers have few therapeutic molecular targets, clarification of key molecular mechanisms of NF-κB signaling would facilitate the development of more effective therapy. In this report, we show that Tob, a member of the Tob/BTG family of antiproliferative proteins, acts as a negative regulator of the NF-κB signal in breast cancer. Studies with 35 human breast cancer cell lines reveal that Tob expression is negatively correlated with NF-κB activity. Analysis of The Cancer Genome Atlas (TCGA) database of clinical samples reveals an inverse correlation between Tob expression and NF-κB activity. Tob knockdown in human breast cancer cells promoted overactivation of NF-κB upon TNF-α treatment, whereas overexpression of Tob inhibited TNF-α stimulation-dependent NF-κB activation. Mechanistically, Tob associates with the TNF receptor complex I and consequently inhibits RIPK1 polyubiquitylation, leading to possible prevention of overwhelming activation of NF-κB.

    DOI: 10.1038/s41417-025-00897-6

    PubMed

    researchmap

  • Metformin synergizes with PD-1 blockade to promote normalization of tumor vessels via CD8T cells and IFNγ. Reviewed International journal

    Miho Tokumasu, Mikako Nishida, Weiyang Zhao, Ruoyu Chao, Natsumi Imano, Nahoko Yamashita, Kyoko Hida, Hisamichi Naito, Heiichiro Udono

    Proceedings of the National Academy of Sciences of the United States of America   121 ( 30 )   e2404778121   2024.7

     More details

    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

    Tumor blood vessels are highly leaky in structure and have poor blood perfusion, which hampers infiltration and function of CD8T cells within tumor. Normalizing tumor vessels is thus thought to be important in promoting the flux of immune T cells and enhancing ant-tumor immunity. However, how tumor vasculature is normalized is poorly understood. Metformin (Met) combined with ant-PD-1 therapy is known to stimulate proliferation of and to produce large amounts of IFNγ from tumor-infiltrating CD8T lymphocytes (CD8TILs). We found that the combination therapy promotes the pericyte coverage of tumor vascular endothelial cells (ECs) to improve blood perfusion and that it suppresses the hyperpermeability through the increase of VE-cadherin. Peripheral node addressin(PNAd) and vascular cell adhesion molecule (VCAM)-1, both implicated to promote tumor infiltration of CD8T cells, were also increased. Importantly, tumor vessel normalization, characterized as the reduced 70-kDa dextran leakage and the enhancement of VE-cadherin and VCAM-1, were canceled by anti-CD8 Ab or anti-IFNγ Ab injection to mice. The increased CD8TILs were also abrogated by anti-IFNγ Ab injection. In vascular ECs, flow cytometry analysis revealed that pSTAT1 expression was found to be associated with VE-cadherin expression. Moreover, in vitro treatment with Met and IFNγ enhanced VE-cadherin and VCAM-1 on human umbilical vein endothelial cells (HUVECs). The Kaplan-Meier method revealed a correlation of VE-cadherin or VCAM-1 levels with overall survival in patients treated with immune checkpoint inhibitors. These data indicate that IFNγ-mediated cross talk of CD8TILs with tumor vessels is important for creating a better tumor microenvironment and maintaining sustained antitumor immunity.

    DOI: 10.1073/pnas.2404778121

    PubMed

    researchmap

  • Nutrient Condition in the Microenvironment Determines Essential Metabolisms of CD8(+) T Cells for Enhanced IFN gamma Production by Metformin Reviewed

    Ruoyu Chao, Mikako Nishida, Nahoko Yamashita, Miho Tokumasu, Weiyang Zhao, Ikuru Kudo, Heiichiro Udono

    FRONTIERS IN IMMUNOLOGY   13   2022.6

     More details

    Language:English   Publishing type:Research paper (scientific journal)   Publisher:FRONTIERS MEDIA SA  

    Metformin (Met), a first-line drug for type 2 diabetes, lowers blood glucose levels by suppressing gluconeogenesis in the liver, presumably through the liver kinase B1-dependent activation of AMP-activated protein kinase (AMPK) after inhibiting respiratory chain complex I. Met is also implicated as a drug to be repurposed for cancers; its mechanism is believed identical to that of gluconeogenesis inhibition. However, AMPK activation requires high Met concentrations at more than 1 mM, which are unachievable in vivo. The immune-mediated antitumor response might be the case in a low dose Met. Thus, we proposed activating or expanding tumor-infiltrating CD8(+) T cells (CD8TILs) in a mouse model by orally administering Met in free drinking water. Here we showed that Met, at around 10 mu M and a physiologically relevant concentration, enhanced production of IFN gamma,TNF alpha and expression of CD25 of CD8(+) T cells upon TCR stimulation. Under a glucose-rich condition, glycolysis was exclusively involved in enhancing IFN gamma production. Under a low-glucose condition, fatty acid oxidation or autophagy-dependent glutaminolysis, or both, was also involved. Moreover, phosphoenolpyruvate carboxykinase 1 (PCK1), converting oxaloacetate to phosphoenolpyruvate, became essential. Importantly, the enhanced IFN gamma production was blocked by a mitochondrial ROS scavenger and not by an inhibitor of AMPK. In addition, IFN gamma production by CD8TILs relied on pyruvate translocation to the mitochondria and PCK1. Our results revealed a direct effect of Met on IFN gamma production of CD8(+) T cells that was dependent on differential metabolic pathways and determined by nutrient conditions in the microenvironment.

    DOI: 10.3389/fimmu.2022.864225

    Web of Science

    researchmap

  • Blocking EP4 down-regulates tumor metabolism and synergizes with anti-PD-1 therapy to activate natural killer cells in a lung adenocarcinoma model Reviewed

    Miho Tokumasu, Mikako Nishida, Takamasa Kawaguchi, Ikuru Kudo, Tohru Kotani, Kazuhiko Takeda, Takao Yoshida, Heiichiro Udono

    INTERNATIONAL IMMUNOLOGY   34 ( 6 )   293 - 302   2022.6

     More details

    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:OXFORD UNIV PRESS  

    Prostaglandin E2 (PGE2), a product of the cyclooxygenase (COX) pathway, is produced by tumors and surrounding stromal cells. It stimulates tumor progression, promotes angiogenesis and suppresses the anti-tumor response. Pharmacological inhibition of PGE2 synthesis has been shown to suppress tumor initiation and growth in vivo. In the current study, we demonstrated that the growth of the Ptgs2-deficient 3LL lung adenocarcinoma cell line was down-regulated in vivo through natural killer (NK) cell activation and a reduction in the population of polymorphonuclear leukocyte-myeloid-derived suppressor cells (PMN-MDSCs) and tumor-associated macrophages (TAMs). On the basis of these results, the therapeutic effect of ONO-AE3-208 (EP4i), an inhibitor of EP4 (a PGE2 receptor), combined with anti-PD-1 antibody was evaluated. EP4i, but not anti-PD-1 antibody, decreased tumor metabolism including glycolysis, fatty acid oxidation and oxidative phosphorylation. EP4i induced IFN gamma production from only NK cells (not from T cells) and a shift from M2-like to M1-like macrophages in TAMs. These effects were further enhanced by anti-PD-1 antibody treatment. Although CD8 T-cell infiltration was increased, IFN gamma production was not significantly altered, even with combination therapy. Tumor hypoxia was ameliorated by either EP4i or anti-PD-1 antibody treatment, which was further affected by the combination. Normalization of tumor vessels was significant only for the combination therapy. The results indicated a novel effect of EP4i for the metabolic reprogramming of tumors and revealed unique features of EP4i that can synergize with anti-PD-1 antibody to promote IFN gamma production by NK cells, polarize TAMs into the M1 phenotype, and reduce hypoxia through normalization of the tumor vasculature.

    DOI: 10.1093/intimm/dxac004

    Web of Science

    researchmap

  • Post-transcriptional Stabilization of Ucp1 mRNA Protects Mice from Diet-Induced Obesity Reviewed

    Akinori Takahashi, Shungo Adachi, Masahiro Morita, Miho Tokumasu, Tohru Natsume, Toru Suzuki, Tadashi Yamamoto

    CELL REPORTS   13 ( 12 )   2756 - 2767   2015.12

     More details

    Language:English   Publishing type:Research paper (scientific journal)   Publisher:CELL PRESS  

    Uncoupling protein 1 (Ucp1) contributes to thermogenesis, and its expression is regulated at the transcriptional level. Here, we show that Ucp1 expression is also regulated post-transcriptionally. In inguinal white adipose tissue (iWAT) of mice fed a high-fat diet (HFD), Ucp1 level decreases concomitantly with increases in Cnot7 and its interacting partner Tob. HFD-fed mice lacking Cnot7 and Tob express elevated levels of Ucp1 mRNA in iWAT and are resistant to diet-induced obesity. Ucp1 mRNA has an elongated poly(A) tail and persists in iWAT of Cnot7(-/-) and/or Tob(-/-) mice on a HFD. Ucp1 3'-UTR-containing mRNA is more stable in cells expressing mutant Tob that is unable to bind Cnot7 than in WT Tob-expressing cells. Tob interacts with BRF1, which binds to an AU-rich element in the Ucp1 3'-UTR. BRF1 knockdown partially restores the stability of Ucp1 3'-UTR-containing mRNA. Thus, the Cnot7-Tob-BRF1 axis inhibits Ucp1 expression and contributes to obesity.

    DOI: 10.1016/j.celrep.2015.11.056

    Web of Science

    researchmap

  • CNOT3 suppression promotes necroptosis by stabilizing mRNAs for cell death-inducing proteins Reviewed

    Toru Suzuki, Chisato Kikuguchi, Sahil Sharma, Toshio Sasaki, Miho Tokumasu, Shungo Adachi, Tohru Natsume, Yumi Kanegae, Tadashi Yamamoto

    SCIENTIFIC REPORTS   5   2015.10

     More details

    Language:English   Publishing type:Research paper (scientific journal)   Publisher:NATURE PUBLISHING GROUP  

    The CCR4-NOT complex is conserved in eukaryotes and is involved in mRNA metabolism, though its molecular physiological roles remain to be established. We show here that CNOT3-depleted mouse embryonic fibroblasts (MEFs) undergo cell death. Levels of other complex subunits are decreased in CNOT3-depleted MEFs. The death phenotype is rescued by introduction of wild-type (WT), but not mutated CNOT3, and is not suppressed by the pan-caspase inhibitor, zVAD-fluoromethylketone. Gene expression profiling reveals that mRNAs encoding cell death-related proteins, including receptor-interacting protein kinase 1 (RIPK1) and RIPK3, are stabilized in CNOT3-depleted MEFs. Some of these mRNAs bind to CNOT3, and in the absence of CNOT3 their poly(A) tails are elongated. Inhibition of RIPK1-RIPK3 signaling by a short-hairpin RNA or a necroptosis inhibitor, necrostatin-1, confers viability upon CNOT3-depleted MEFs. Therefore, we conclude that CNOT3 targets specific mRNAs to prevent cells from being disposed to necroptotic death.

    DOI: 10.1038/srep14779

    Web of Science

    researchmap

▼display all

Books

  • がん免疫ペディア : 腫瘍免疫学・がん免疫療法の全てをまるごと理解!

    吉村, 清( Role: Contributor ,  T細胞におけるグルタミン代謝活性化機構)

    羊土社  2022.3  ( ISBN:9784758121194

     More details

    Total pages:220p   Language:Japanese

    CiNii Books

    researchmap

MISC

  • メトホルミンと抗PD-1抗体の併用は腫瘍浸潤CD8T細胞とIFNγを介して腫瘍血管の正常化を亢進する

    徳増美穂, 西田充香子, ZHAO Weiyang, CHAO Ruoyu, 今野なつみ, 山下奈穂子, 樋田京子, 内藤尚道, 鵜殿平一郎

    日本分子生物学会年会プログラム・要旨集(Web)   47th   2024

  • 増大特集 代謝 Ⅳ.代謝と免疫 代謝介入による抗腫瘍免疫の変化

    鵜殿 平一郎, Ruoyu Chao, 徳増 美穂, 西田 充香子

    生体の科学   74 ( 5 )   474 - 475   2023.10

     More details

    Publisher:株式会社医学書院  

    DOI: 10.11477/mf.2425201760

    researchmap

  • がんと代謝—Cancer and metabolism

    徳増 美穂, 鵜殿 平一郎

    皮膚科 = Dermatology / 皮膚科編集委員会 編   4 ( 1 )   66 - 73   2023.7

     More details

    Language:Japanese   Publisher:科学評論社  

    CiNii Books

    researchmap

  • 肺腺癌マウスのEP-4阻害剤と抗PD-1抗体の併用療法の解析

    徳増 美穂, 西田 充香子, 川口 高正, 吉田 隆雄, 工藤 生, 鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集   25回   114 - 114   2021.5

     More details

    Language:Japanese   Publisher:日本がん免疫学会  

    researchmap

  • 肺腺がん細胞のCOX-2欠損はその固形腫瘍形成と増殖を抑制する(COX-2 deficiency in lung adenocarcinoma cells suppresses solid tumor formation and slow down the growth in vivo)

    徳増 美穂, 山崎 千尋, 西田 充香子, 鵜殿 平一郎

    日本癌学会総会記事   78回   P - 2275   2019.9

     More details

    Language:English   Publisher:(一社)日本癌学会  

    researchmap

  • Negative regulation of NF-kappa B signaling by Tobl in breast cancer

    Miho Tokumasu, Mizuki Yamamoto, Jyun Nakayama, Kentaro Semba, Jyunichiro Inoue, Tadashi Yamamoto

    CANCER SCIENCE   109   205 - 205   2018.1

     More details

    Language:English   Publishing type:Research paper, summary (international conference)   Publisher:WILEY  

    Web of Science

    researchmap

  • 乳癌細胞においてTob1の発現とNF-κBシグナル活性は負に相関する

    徳増 美穂, 呉羽 拓, 山本 瑞生, 中山 淳, 仙波 健太郎, 井上 純一郎, 山本 雅

    生命科学系学会合同年次大会   2017年度   [1P - 1043]   2017.12

     More details

    Language:Japanese   Publisher:生命科学系学会合同年次大会運営事務局  

    researchmap

  • 乳癌におけるTob1の発現はNF-κB経路を負に制御する

    徳増 美穂, 山本 瑞生, 中山 淳, 仙波 憲太郎, 井上 純一郎, 山本 雅

    日本癌学会総会記事   76回   P - 1081   2017.9

     More details

    Language:English   Publisher:(一社)日本癌学会  

    researchmap

  • 低温菌Shewanella livingstonensis Ac10の細胞分裂関連タンパク質の機能解析

    永久由利絵, 青柳美穂, 川本純, 江崎信芳, 栗原達夫

    京都大学低温物質科学研究センター誌   ( 22 )   2013

  • 低温菌Shewanella livingstonensis Ac10の細胞分裂に関わる膜タンパク質の機能解析

    永久由利絵, 青柳美穂, 川本純, 江崎信芳, 栗原達夫

    日本農芸化学会大会講演要旨集(Web)   2012   2012

  • 低温菌Shewanella livingstonensis Ac10の細胞分裂関連タンパク質の機能解析

    永久由利絵, 青柳美穂, 川本純, 江崎信芳, 栗原達夫

    日本生化学会大会(Web)   85th   2012

  • 低温菌Shewanella livingstonensis Ac10の細胞分裂に関与するABCトランスポーターの解析

    青柳美穂, 川本純, 栗原達夫, 江崎信芳

    日本農芸化学会大会講演要旨集   2011   2011

  • 低温菌Shewanella livingstonensis Ac10の細胞分裂におけるEPA含有リン脂質の生理機能

    青柳美穂, 川本純, 栗原達夫, 江崎信芳

    生化学   2010

▼display all

Presentations

  • Metformin synergizes with PD-1 blockade to promote normalization of tumor vessels via CD8T cells and IFNγ.

    2024.12.3 

     More details

    Presentation type:Poster presentation  

    researchmap

  • メトホルミンと抗PD-1抗体の併用は腫瘍浸潤CD8T細胞とIFNγを介して腫瘍血管の正常化を亢進する

    徳増美穂, 西田充香子, Weiyang Zhao, Ruoyu Chao, 今野なつみ, 山下奈穂子, 樋田京子, 内藤尚道, 鵜殿平一郎

    第47回 日本分子生物学会年会  2024.11.29 

     More details

    Presentation type:Poster presentation  

    researchmap

  • Analysis of cancer immunotherapy using PGE2 blockade in a mouse lung adenocarcinoma model.

    2024.3.6 

     More details

    Presentation type:Oral presentation (general)  

    researchmap

Awards

  • Outstanding Merit Award 2023

    2023   Japan Society for Immunology   “Blocking EP4 down-regulates tumor metabolism and synergizes with anti-PD-1 therapy to activate natural killer cells in a lung adenocarcinoma model

    Miho Tokumasu, Mikako Nishida, Takamasa Kawaguchi, Ikuru Kudo, Tohru Kotani, Kazuhiko Takeda, Takao Yoshida, Heiichiro Udono

     More details

Research Projects

  • 固形腫瘍の代謝不均一性の分子基盤の解明

    2023.12 - 2024.03

    岡山大学ダイバーシティ推進本部  女性研究者研究費支援事業(若手型) 

      More details

    Authorship:Principal investigator 

    researchmap

  • 免疫細胞が制御する腫瘍微小環境の代謝不均一性の分子基盤の解明

    Grant number:23K19540  2023.08 - 2025.03

    日本学術振興会  科学研究費助成事業  研究活動スタート支援

    徳増 美穂

      More details

    Grant amount:\2860000 ( Direct expense: \2200000 、 Indirect expense:\660000 )

    researchmap

 

Class subject in charge

  • Immunology (2024academic year) special  - その他

  • Practice in Immunology (2024academic year) special  - その他

  • Practicals: Immunology (2024academic year) special  - その他

  • Research Projects: Immunology (2024academic year) special  - その他

  • Research Projects and Practicals: Immunology I (2024academic year) special  - その他

  • Lecture and Research Projects: Immunology I (2024academic year) special  - その他

  • Research Projects and Practicals: Immunology II (2024academic year) special  - その他

  • Lecture and Research Projects: Immunology II (2024academic year) special  - その他

  • Parasitorogy (2024academic year) special  - その他

  • Cancer Microenvironment Management (2023academic year) special  - その他

  • Immunology (2023academic year) special  - その他

  • Practice in Immunology (2023academic year) special  - その他

  • Practicals: Immunology (2023academic year) special  - その他

  • Research Projects: Immunology (2023academic year) special  - その他

  • Research Projects and Practicals: Immunology I (2023academic year) special  - その他

  • Lecture and Research Projects: Immunology I (2023academic year) special  - その他

  • Research Projects and Practicals: Immunology II (2023academic year) special  - その他

  • Lecture and Research Projects: Immunology II (2023academic year) special  - その他

  • Parasitorogy (2023academic year) special  - その他

▼display all

 

Media Coverage

  • 免疫T細胞によるインターフェロンγを介した腫瘍血管正常化を発見!~メトホルミンと抗PD-1抗体併用は血管を正常化し抗がん活性を高める~ Internet

    岡山大学  https://www.okayama-u.ac.jp/tp/release/release_id1261.html  2024.7

     More details