Development of novel IL-26 targeted therapeutic approaches for cancer metastasis

• Project/Area Number: 19K21278
• Project/Area Number (Other): 18H06169 (2018)
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund (2019); Single-year Grants (2018)
• Review Section: 0901:Oncology and related fields
• Research Institution: Juntendo University
• Principal Investigator: Takumi Itoh 順天堂大学, 医学(系)研究科(研究院), 博士研究員 (80811835)
• Project Period (FY): 2018-08-24 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: Th17 / IL-26 / 炎症性サイトカイン / 悪性黒色腫 / 癌微小環境 / 腫瘍免疫 / 癌転移 / 上皮間葉転換

Outline of Research at the Start

本研究ではIL-26分子標的治療の有効性評価を行うため、高転移性悪性黒色腫における癌微小環境中で産生されるIL-26が腫瘍の高転移能獲得のどのステージに関与しているのか明らかにする。これにより、最も予後の悪い遠隔転移性の悪性黒色腫を根絶する新たな分子標的療法を提供するとともに様々な転移性癌の治療応用と微小環境におけるTh17細胞の役割の解明にも繋がることが期待される。

Outline of Final Research Achievements

We recently show that the Th17 cytokine IL-26 promotes angiogenesis and activates fibroblasts in inflammatory conditions, while its role in tumor microenvironment still remains to be elucidated.
Since IL-26 is absent in rodents, human IL-26 transgenic (hIL-26Tg) mice were used in our study. After subcutaneous transplantation of murine melanoma B16F10 cells into hIL-26Tg mice, sarcoma-like transformation, upregulation of Snail1were observed. To investigate the metastatic potential of IL-26-educated B16F10, B16F10 cells resected from the subcutaneous tissue of hIL-26Tg mice were intravenously injected into C57BL/6 wild-type mice. Lung metastasis was prominently observed following injection of IL-26-educated cells as compared with control mice-derived cells. Our results suggest that IL-26 promotes melanoma metastasis through Snail1-mediated epithelial-mesenchymal transition, and blockade of IL-26 appears to be a promising novel therapeutic strategy for the control of tumor metastasis.

Academic Significance and Societal Importance of the Research Achievements

本研究ではヒトIL-26トランスジェニックマウスを用いた担癌モデルを作製してIL-26の機能の詳細な解明を行っており、これまで明らかにならなかった癌微小環境でのIL-26の機能を明らかにし、IL-26が癌の転移能を亢進させる新しいメカニズムを明らかにした。これにより、根治が難しい癌転移における新しい治療の開発や免疫治療法の開発に繋がることが期待される。

Research Products

• [Journal Article] Stromal fibroblasts induce metastatic tumor cell clusters via epithelial-mesenchymal plasticity. (2019)
  • Author(s): Matsumura Y, Ito Y, Mezawa Y, Sulidan K, Daigo Y, Hiraga T, Mogushi K, Wali N, Suzuki H, Itoh T, Miyagi Y, Yokose T, Shimizu S, Takano A, Terao Y, Saeki H, Ozawa M, Abe M, Takeda S, Okumura K, Habu S, Hino O, Takeda K, Hamada M, Orimo A.
  • Journal Title: Life Sci Alliance Volume: 2(4):e201900425. Issue: 4 Pages: 1-24
  • DOI: 10.26508/lsa.201900425
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Characterization of novel anti-IL-26 neutralizing monoclonal antibodies for the treatment of inflammatory diseases including psoriasis. (2019)
  • Author(s): Hatano R, Itoh T, Otsuka H, Okamoto S, Komiya E, Iwata S, Aune TM, Dang NH, Kuwahara-Arai K, Ohnuma K, Morimoto C.
  • Journal Title: mabs. Volume: 11 Issue: 8 Pages: 1428-1442
  • DOI: 10.1080/19420862.2019.1654305
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development of novel monoclonal antibodies with specific binding affinity for denatured human CD26 in formalin-fixed paraffin-embedded and decalcified specimens (2019)
  • Author(s): Hatano R, Yamada T, Madokoro H, Otsuka H, Komiya E, Itoh T, Narita Y, Iwata S, Yamazaki H, Matsuoka S, Dang NH, Morimoto C
  • Journal Title: PLoS ONE Volume: 14 Issue: 6 Pages: e0218330-e0218330
  • DOI: 10.1371/journal.pone.0218330
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Biological effects of IL-26 on T cell-mediated skin inflammation, including psoriasis. (2019)
  • Author(s): Itoh T, Hatano R, Komiya E, Otsuka H, Narita Y, Aune TM, Dang NH, Matsuoka S, Naito H, Tominaga M, Takamori K, Morimoto C, Ohnuma K.
  • Journal Title: J Invest Dermatol Volume: 139 Issue: 4 Pages: 878-889
  • DOI: 10.1016/j.jid.2018.09.037
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Possible regulation of mechanical itch by CD26/DPPIV (2019)
  • Author(s): 古宮 栄利子, 波多野良, 伊藤匠, 大塚春奈, 鎌田弥生, 本田耕太郎, 外山扇雅, カタリナサギタモニアガ, 大沼圭, 冨永光俊, 森本幾夫, 高森建二
  • Organizer: 10th World Congress on Itch (WCI)
  • Int'l Joint Research
• [Presentation] Possible role for CD26/DPPIV in regulating mechanical itch (Alloknesis) (2019)
  • Author(s): 古宮 栄利子, 波多野良, 伊藤匠, 大塚春奈, 鎌田弥生, 本田耕太郎, 外山扇雅, カタリナサギタモニアガ, 大沼圭, 冨永光俊, 森本幾夫, 高森建二
  • Organizer: 28th European Academy of Dermatology and Venereology (EADV) Congress
  • Int'l Joint Research
• [Presentation] CD26/ dipeptidyl-peptidase IVは機械的かゆみの抑制因子である (2019)
  • Author(s): 古宮 栄利子, 波多野良, 冨永光俊, 伊藤匠, 鎌田弥生, 本田耕太郎, 外山扇雅, カタリナサギタモニアガ, 大沼圭, 森本幾夫, 高森建二
  • Organizer: 日本病態プロテアーゼ学会
• [Presentation] CD26/DPPIV regulates mechanical itch by enzymatic degradation of mu-opioid receptor ligands (2019)
  • Author(s): 古宮 栄利子, 波多野良, 伊藤匠, 大塚春奈, 大沼圭, 冨永光俊, 森本幾夫, 高森建二
  • Organizer: 24th World Congress of Dermatology (WCD)
  • Int'l Joint Research
• [Presentation] 加齢皮膚で誘発される機械的かゆみ調節機構の解明 (2019)
  • Author(s): 古宮 栄利子,冨永光俊, 波多野良, 伊藤匠, 大塚春奈, 本田耕太郎, 外山扇雅, 鎌田弥生, 大沼圭, 森本幾夫, 高森建二
  • Organizer: 第15回加齢皮膚医学研究会
• [Presentation] 機械的かゆみの調節メカニズムの解明 (2018)
  • Author(s): 古宮 栄利子, 波多野良, 大塚春奈, 伊藤匠, 松田浩則, 須賀康, 大沼圭, 冨永光俊, 森本幾夫, 髙森建二
  • Organizer: 第82回日本皮膚科学会東京支部
• [Remarks] 乾癬などの炎症性皮膚疾患が悪化するメカニズムを解明
  • URL: https://www.juntendo.ac.jp/news/20190417-01.html