Molecular understanding of tumor immunology of malignant pleural mesothelioma targeting human CD26/DPPIV molecule.

• Project/Area Number: 20K07683
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Juntendo University
• Principal Investigator: Hatano Ryo 順天堂大学, 大学院医学研究科, 特任准教授 (30638789)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: CD26/DPP4 / 悪性胸膜中皮腫 / ヒト化抗CD26抗体 / 腫瘍免疫 / ヒトT細胞 / 全身性エリテマトーデス / 悪性中皮腫 / 胸水 / 免疫制御 / CD26/DPPIV / 免疫チェックポイント分子

Outline of Research at the Start

悪性胸膜中皮腫は現時点で有効な治療法がない難治性・希少がんである。本研究はヒトT細胞が持つCD26/DPPIV分子に着目し、悪性胸膜中皮腫における腫瘍免疫制御の多様性の一端を明らかにすること、CD26/Caveolin-1経路が腫瘍免疫応答、悪性胸膜中皮腫の病態にいかに関与しているかを示すことを目的とする。これにより、申請者のグループが現在、悪性胸膜中皮腫に対する臨床試験を実施している抗CD26抗体療法の作用機序の更なる解明にも繋がることが期待できる。

Outline of Final Research Achievements

CD26 is a human T cell costimulatory molecule with known dipeptidyl peptidase 4 (DPP4) activity and is expressed on both T cells and various types of tumor cells. We have had a long-standing interest in the role of CD26 in cancer biology and immune regulation and developed a humanized anti-CD26 monoclonal antibody (mAb). The phase I/II clinical trial of this mAb for malignant pleural mesothelioma (MPM) has been finished. In addition to the direct anti-tumor effects of anti-CD26 mAb on CD26-expressing tumors, this mAb is expected to positively regulate tumor immunity.
In the present study, we investigate the expression pattern of CD26 and the response to CD26-mediated costimulation of human T cells in the pleural effusion that are located near MPM to clarify how CD26 molecule is involved in the regulation of tumor immunity. The aim of the study is to elucidate the novel mechanisms of action of anti-CD26 mAb and to establish anti-CD26 mAb therapy for the refractory tumors including MPM.

Academic Significance and Societal Importance of the Research Achievements

がん細胞自身や抑制性の免疫細胞の影響により、がん細胞周囲のT細胞と末梢血T細胞とでは性質が大きく異なり、がん組織の免疫細胞の機能解析が推奨されているが、新鮮な組織を得る難しさや細胞数の制限など研究上の制約も多いことが課題である。
がん細胞の近位に存在する胸水中T細胞を用いた本研究により、CD26分子が腫瘍免疫の制御にいかに関与しているかを明らかにし、CD26抗体の新たな抗腫瘍作用メカニズムの解明に貢献することで、悪性胸膜中皮腫を中心とした難治性がんに対する革新的なCD26抗体療法の確立を目指す。

Research Products

• [Journal Article] Anti-glomerular Basement Membrane Disease Concomitant with MPO-ANCA Positivity Concurrent with High Serum Levels of Interleukin-26 Following Coronavirus Disease 2019 Vaccination (2023)
  • Author(s): Kobayashi S, Fugo K, Hatano R, Yamazaki K, Morimoto C, Terawaki H.
  • Journal Title: Internal Medicine Volume: 62 Issue: 7 Pages: 1043-1048
  • DOI: 10.2169/internalmedicine.1027-22
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2023-04-01
  • Peer Reviewed / Open Access
• [Journal Article] Functional roles of <scp>CD26</scp> / <scp>DPP4</scp> in bleomycin‐induced pulmonary fibrosis (2023)
  • Author(s): Koyanagi Yu、Kawasaki Takeshi、Kasuya Yoshitoshi、Hatano Ryo、Sato Shun、Takahashi Yukiko、Ohnuma Kei、Morimoto Chikao、Dudek Steven M.、Tatsumi Koichiro、Suzuki Takuji
  • Journal Title: Physiological Reports Volume: 11 Issue: 6
  • DOI: 10.14814/phy2.15645
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Humanized anti-IL-26 monoclonal antibody as a novel targeted therapy for chronic graft-versus-host disease (2022)
  • Author(s): Hatano Ryo、Itoh Takumi、Otsuka Haruna、Saeki Harumi、Yamamoto Ayako、Song Dan、Shirakawa Yuki、Iyama Satoshi、Sato Tsutomu、Iwao Noriaki、Harada Norihiro、Aune Thomas M.、Dang Nam H.、Kaneko Yutaro、Yamada Taketo、Morimoto Chikao、Ohnuma Kei
  • Journal Title: American Journal of Transplantation Volume: 22 Issue: 12 Pages: 2804-2820
  • DOI: 10.1111/ajt.17178
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Peripheral endomorphins drive mechanical alloknesis under the enzymatic control of CD26/DPPIV (2022)
  • Author(s): Komiya Eriko、Tominaga Mitsutoshi、Hatano Ryo、Kamikubo Yuji、Toyama Sumika、Sakairi Hakushun、Honda Kotaro、Itoh Takumi、Kamata Yayoi、Tsurumachi Munehiro、Kishi Ryoma、Ohnuma Kei、Sakurai Takashi、Morimoto Chikao、Takamori Kenji
  • Journal Title: Journal of Allergy and Clinical Immunology Volume: 149 Issue: 3 Pages: 1085-1096
  • DOI: 10.1016/j.jaci.2021.08.003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] IL-26 mediates epidermal growth factor receptor-tyrosine kinase inhibitor resistance through endoplasmic reticulum stress signaling pathway in triple-negative breast cancer cells (2021)
  • Author(s): Itoh Takumi、Hatano Ryo、Horimoto Yoshiya、Yamada Taketo、Song Dan、Otsuka Haruna、Shirakawa Yuki、Mastuoka Shuji、Iwao Noriaki、Aune Thomas M.、Dang Nam H.、Kaneko Yutaro、Okumura Ko、Morimoto Chikao、Ohnuma Kei
  • Journal Title: Cell Death and Disease Volume: 12 Issue: 6 Pages: 520-520
  • DOI: 10.1038/s41419-021-03787-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Serum soluble CD26/DPP4 titer variation is a potential prognostic biomarker in cancer therapy with a humanized anti-CD26 antibody. (2021)
  • Author(s): Kaneko Y, Hatano R, Hirota N, Isambert N, Trillet-Lenoir V, You B, Alexandre J, Zalcman G, Valleix F, Podoll T, Umezawa Y, Takao S, Iwata S, Hosono O, Taguchi T, Yamada T, Dang NH, Ohnuma K, Angevin E, Morimoto C.
  • Journal Title: Biomark Res Volume: 9 Issue: 1 Pages: 21-21
  • DOI: 10.1186/s40364-021-00273-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Single-cell atlas of colonic CD8+ T-cells in ulcerative colitis. (2020)
  • Author(s): Corridoni D, Antanaviciute A, Gupta T, Fawkner-Corbett D, Aulicino A, Jagielowicz M, Parikh K, Repapi E, Taylor S, Ishikawa D, Hatano R, Yamada T, Xin W, Slawinki H, Bowden R, Napolitani G, Brain O, Morimoto C, Koohy H, Simmons A.
  • Journal Title: Nat Med Volume: 26 Issue: 9 Pages: 1480-1490
  • DOI: 10.1038/s41591-020-1003-4
  • Peer Reviewed / Int'l Joint Research
• [Presentation] IL-26 facilitates cartilage destruction and infiltration of inflammatory cells into synovium in a collagen induced arthritis model. (2022)
  • Author(s): Shirakawa Y, Hatano R, Itoh T, Otsuka H, Okumura K, Morimoto C.
  • Organizer: 第51回日本免疫学会学術集会
• [Presentation] CD26/dipeptidyl-peptidase IVは機械的かゆみの調節因子である. (2021)
  • Author(s): 古宮栄利子, 冨永光俊, 波多野良, 外山扇雅, 伊藤匠, 鎌田弥生, 本田耕太郎, 大沼圭, 森本幾夫, 高森建二.
  • Organizer: 第26回日本病態プロテアーゼ学会, Web開催, 口頭
• [Presentation] Anti-interleukin-26 therapy for the control of chronic inflammation in GVHD. (2021)
  • Author(s): Hatano R, Otsuka H, Itoh T, Saeki H, Yamamoto A, Shirakawa Y, Iyama S, Iwao N, Sato T, Yamada T, Morimoto C, Ohnuma K.
  • Organizer: 第83回日本血液学会, Web開催, 口頭
• [Presentation] CD26/DPPIV regulates mechanical alloknesis at the periphery. (2021)
  • Author(s): Komiya E, Tominaga M, Hatano R, Itoh T, Honda K, Toyama S, Kamata Y, Otsuka H, Ohnuma K, Morimoto C, Takamori K.
  • Organizer: 11th World Congress on Itch (WCI), Web開催, 口頭
  • Int'l Joint Research
• [Presentation] Mu-opioid ligand endomorphin induces alloknesis at the periphery. (2021)
  • Author(s): Komiya E, Tominaga M, Hatano R, Itoh T, Honda K, Toyama S, Kamata Y, Otsuka H, Ohnuma K, Morimoto C, Takamori K.
  • Organizer: 第46回日本研究皮膚科学会, Web開催, 口頭
• [Presentation] Endomorphin preferentially induces mechanical alloknesis under the control of DPPIV enzyme. (2020)
  • Author(s): Eriko Komiya, Ryo Hatano, Takumi Itoh, Kotaro Honda, Yayoi Kamata, Sumika Toyama, Catharina Sagita Moniaga, Haruna Otsuka, Nobuaki Takahashi, Kei Ohnuma, Mitsutoshi Tominaga, Chikao Morimoto, Kenji Takamori.
  • Organizer: 第45回日本研究皮膚科学会、WEB開催
• [Remarks] 順天堂大学大学院医学研究科 免疫病・がん先端治療学講座 ホームページ
  • URL: https://sites.google.com/view/menekibyougan/
• [Remarks] 順天堂大学大学院医学研究科 免疫病・がん先端治療学講座ホームページ
  • URL: https://www.juntendo.ac.jp/graduate/laboratory/labo/immunity_cancer/
• [Patent(Industrial Property Rights)] 抗CD26抗体と免疫チェックポイント阻害剤との併用療法. (2022)
  • Inventor(s): 森本幾夫、波多野良、大沼圭、金子有太郎.
  • Industrial Property Rights Holder: ワイズ・エー・シー株式会社、学校法人順天堂
  • Industrial Property Rights Type: 特許
  • Filing Date: 2022
  • Overseas
• [Patent(Industrial Property Rights)] 抗CD26抗体と免疫チェックポイント阻害剤との併用療法. (2021)
  • Inventor(s): 森本幾夫、波多野良、大沼圭、金子有太郎.
  • Industrial Property Rights Holder: ワイズ・エー・シー株式会社、学校法人順天堂
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2021-091761
  • Filing Date: 2021
• [Patent(Industrial Property Rights)] 抗癌剤への抵抗性改善剤. (2021)
  • Inventor(s): 森本幾夫、大沼圭、波多野良、伊藤匠、金子有太郎.
  • Industrial Property Rights Holder: ワイズ・エー・シー株式会社、学校法人順天堂
  • Industrial Property Rights Type: 特許
  • Filing Date: 2021
  • Overseas
• [Patent(Industrial Property Rights)] 抗癌剤への抵抗性改善剤 (2020)
  • Inventor(s): 森本幾夫、大沼圭、波多野良、伊藤匠、金子有太郎.
  • Industrial Property Rights Holder: ワイズ・エー・シー株式会社、学校法人順天堂
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2020-099449
  • Filing Date: 2020