The development of the efficacious anti-tumor DC therapies using TGF-beta antagonists

• Project/Area Number: 17K15735
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Immunology
• Research Institution: Tokyo Medical University
• Principal Investigator: Yoon Jeong-Hwan 東京医科大学, 医学部, 兼任助教 (30748885)
• Research Collaborator: MAMURA Mizuko
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: dendritic cell / TGF-β / Smad / differentiation / anti-tumor immunity / 免疫学 / 免疫監視・腫瘍免疫

Outline of Final Research Achievements

Molecular mechanisms how TGF-β regulates differentiation and maturation of dendritic cell (DC) subsets: Signaling molecules of TGF-β, Smads are usually ubiquitously expressed in normal cells. However, I have found that selective repression of one of the R-Smads: Smad3 directs conventional DC (cDC), whereas its maintenance directs plasmacytoid DC (pDC) differentiation. I have also clarified the mechanisms how Smad3 is repressed or maintained for cDC and pDC differentiation.
The mechanisms how systemic TGF-β antagonists exert dose-dependent divergent effects on tumor immunity: I have found that the treatment with high-dose activin receptor-like kinase (ALK)5 inhibitor exacerbated the murine B16 melanoma model by accelerating the Smad-mediated TGF-β signaling via blocking the negative feedback loop.
DC-based anti-tumor immunotherapies using TGF-β antagonists: I have found that the transfer of ALK5 inhibitor-treated DCs is efficacious against the murine B16 melanoma model.

Academic Significance and Societal Importance of the Research Achievements

がんに対する免疫が弱められないようにする免疫チェックポイント阻害薬が有効ながん免疫療法として保険診療で処方できるようになりましたが、副作用や効果が無い場合があります。一方で、がんに対する免疫を強める樹状細胞を用いたがんワクチン療法も開発段階にありますが、治療効果は未確定です。TGF-βというサイトカインはがんに対する免疫が弱めるので、抑えるとがんに対する免疫を強め、免疫チェックポイント阻害薬の効果を高めることが報告されていますが、全身投与では副作用の可能性もあります。本研究成果は従来の樹状細胞ワクチンより簡単な方法で治療効果が高く副作用が少ないがん免疫療法の開発につながる可能性があります。

Research Products

• [Journal Article] Repression of Smad3 by Stat3 and c-Ski/SnoN induces gefitinib resistance in lung adenocarcinoma. (2017)
  • Author(s): Makino Y, Yoon JH, Bae E, Kato M, Miyazawa K, Ohira T, Ikeda N, Kuroda M, Mamura M.
  • Journal Title: Biochem Biophys Res Commun. Volume: 484 Issue: 2 Pages: 269-77
  • DOI: 10.1016/j.bbrc.2017.01.093
  • NAID: 120007134941
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Selection of Smad2 for TGF-β to suppress dendritic cells by STAT3/c-Ski-induced repression of Smad3 (2017)
  • Author(s): Jeong-Hwan Yoon, Eunjin Bae, Katsuko Sudo, Seok Hee Park, Michael Weinstein, Susumu Nakae, Jin Soo Han,InKyu Lee, Ji Hyeon Ju, Takayuki Sumida, Masahiko Kuroda, Keiji Miyazawa, Mitsyasu Kato, Mizuko Mamura
  • Organizer: The American Association for Cancer Research Annual Meeting 2017, Washington DC, USA
  • Int'l Joint Research
• [Presentation] Repression of SMAD3 by STAT3 and c-Ski Is Essential for Conventional Dendritic Cell Differentiation (2017)
  • Author(s): Jeong-Hwan Yoon, Eunjin Bae, Katsuko Sudo, Seok Hee Park, Michael Weinstein, Susumu Nakae, Jin Soo Han,InKyu Lee, Ji Hyeon Ju, Takayuki Sumida, Masahiko Kuroda, Keiji Miyazawa, Mitsyasu Kato, Mizuko Mamura
  • Organizer: The 5th Annual Meeting of the International Cytokine and Interferon Society, Kanazawa, Japan
  • Int'l Joint Research
• [Presentation] Repression of SMAD3 by STAT3 and c-Ski Is Essential for Conventional Dendritic Cell Differentiation (2017)
  • Author(s): Jeong-Hwan Yoon, Eunjin Bae, Katsuko Sudo, Seok Hee Park, Michael Weinstein, Susumu Nakae, Jin Soo Han,InKyu Lee, Ji Hyeon Ju, Takayuki Sumida, Masahiko Kuroda, Keiji Miyazawa, Mitsyasu Kato, Mizuko Mamura
  • Organizer: The 46th Annual Meeting of The Japanese Society for Immunology, Sendai, Japan