Research aimed at developing a new cancer immunotherapy

• Project/Area Number: 18K19466
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 50:Oncology and related fields
• Research Institution: Chiba University
• Principal Investigator: Kimura Motoko 千葉大学, 大学院医学研究院, 准教授 (00345018)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2019: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2018: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: CD69 / がん免疫療法 / 腫瘍浸潤T細胞 / 疲弊 / 抗腫瘍効果 / CD69リガンド / Myl9/12 / CC69 / 抗体療法

Outline of Final Research Achievements

This research is aimed at revealing the role of CD69 molecule on anti-tumor immune responses, and at contributing to establish a new cancer immunotherapy. CD69 has been known to regulate lymphocyte trafficking and migration, and we found that CD69 is expressed on most tumor-specific T cells infiltrated within tumor microenvironment. Importantly, our data showed that tumor growth was significantly reduced in Cd69-deficient mice as well as the mice with anti-CD69 Ab treatment, which was accompanied with enhanced anti-tumor immune responses. Our results show that CD69 is a new target for cancer immunotherapy.

Academic Significance and Societal Importance of the Research Achievements

患者自身の免疫システムを活性化することにより腫瘍を攻撃する「免疫療法」は、近年目覚ましい開発が進められており、今後、さらに大きな発展が期待される。しかしその一方で、現行の免疫チェックポイント阻害剤の適応にならないがん腫や、副作用の問題、禁忌症などがあることから、新たな免疫療法の開発が常に求められている。
本研究は「CD69」というT細胞の動態システムに重要な働きをする分子に着目し、新しいがん免疫療法の確立を目指したものである。従来の免疫チェックポイント阻害薬とは、一線を画した斬新なアイディアを基にしたものであり、学術的意義、社会的意義の高い研究である。

Research Products

• [Journal Article] Differentiation of Pathogenic Th17 Cells Is Negatively Regulated by Let-7 MicroRNAs in a Mouse Model of Multiple Sclerosis (2020)
  • Author(s): Angelou Constance C.、Wells Alexandria C.、Vijayaraghavan Jyothi、Dougan Carey E.、Lawlor Rebecca、Iverson Elizabeth、Lazarevic Vanja、Kimura Motoko Y.、Peyton Shelly R.、Minter Lisa M.、Osborne Barbara A.、Pobezinskaya Elena L.、Pobezinsky Leonid A.
  • Journal Title: Frontiers in Immunology Volume: 10 Pages: 3125-3125
  • DOI: 10.3389/fimmu.2019.03125
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A new therapeutic target: the CD69-Myl9 system in immune responses (2019)
  • Author(s): Kimura Motoko Y.、Koyama-Nasu Ryo、Yagi Ryoji、Nakayama Toshinori
  • Journal Title: Seminars in Immunopathology Volume: - Issue: 3 Pages: 349-358
  • DOI: 10.1007/s00281-019-00734-7
  • Peer Reviewed / Open Access
• [Journal Article] Survival of Naive T Cells Requires the Expression of Let-7 miRNAs (2019)
  • Author(s): Pobezinskaya Elena L.、Wells Alexandria C.、Angelou Constance C.、Fagerberg Eric、Aral Esengul、Iverson Elizabeth、Kimura Motoko Y.、Pobezinsky Leonid A.
  • Journal Title: Frontiers in Immunology Volume: 10 Pages: 955-955
  • DOI: 10.3389/fimmu.2019.00955
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ezh2 controls development of natural killer T cells, which cause spontaneous asthma-like pathology (2019)
  • Author(s): Tumes, D., Hirahara, K., Papadopoulos, M., Shinoda, K., Onodera, A., Kumagai, J., Yip, KH., Pant, H., Kokubo, K., Masahiro, K., Aoki, A., Obata-Ninomiya, K., Yokoyoda, K., Endo, Y., Kimura, MY., Nakayama, T.
  • Journal Title: Journal of Allergy and Clinical Immunology Volume: 0091-6749(19) Issue: 2 Pages: 30340-9
  • DOI: 10.1016/j.jaci.2019.02.024
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The basis of T cell development and lineage choice in the thymus (2018)
  • Author(s): Kimura, M.Y.
  • Journal Title: Chiba medical journal Volume: 94E Issue: 3 Pages: 19-23
  • DOI: 10.20776/S03035476-94E-3-P19
  • NAID: 120006489910
  • URL: https://opac.ll.chiba-u.jp/da/curator/105204/
  • Year and Date: 2018-06-01
  • Peer Reviewed / Open Access
• [Journal Article] CD69 prevents PLZFhi innate precursors from prematurely exiting the thymus and aborting NKT2 cell differentiation (2018)
  • Author(s): Kimura Motoko Y.、Igi Akemi、Hayashizaki Koji、Mita Yukiyoshi、Shinzawa Miho、Kadakia Tejas、Endo Yukihiro、Ogawa Satomi、Yagi Ryoji、Motohashi Shinichiro、Singer Alfred、Nakayama Toshinori
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 3749-3749
  • DOI: 10.1038/s41467-018-06283-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Crucial role of CD69 in anti-tumor immunity through regulating the exhaustion of tumor-infiltrating T cells (2018)
  • Author(s): Mita Y, Kimura MY, Hayashizaki K, Koyama-Nasu R, Ito T, Motohashi S, Okamoto Y & Nakayama T
  • Journal Title: International Immunology Volume: 30 Issue: 12 Pages: 559-567
  • DOI: 10.1093/intimm/dxy050
  • Peer Reviewed / Open Access
• [Presentation] CD69 Biology and Pathology (2020)
  • Author(s): Kimura M.Y., Koyama-Nasu, R., Mita Y., Hayashizaki, K. and Nakayama T.
  • Organizer: 11th International Symposium of IFReC, Immunology at the Forefront
  • Int'l Joint Research / Invited
• [Presentation] CD69 regulates T cell exhaustion at the tumor microenvironment (2019)
  • Author(s): Kimura M.Y.
  • Organizer: First Chiba University - University of Toronto workshop
  • Int'l Joint Research / Invited
• [Presentation] Inhibition of acetyl-CoA carboxylase enhances memory Th2 cell generation and Th2 mediated anti-tumor immunity (2019)
  • Author(s): Koyama-Nasu R., Endo Y., Ito T., Kanno T., Nakajima T., Kimura M.Y. and Nakayama T.
  • Organizer: 第２３回日本がん免疫学会総会
• [Presentation] がん免疫療法の新たなターゲットとしてのCD69の可能性 (2019)
  • Author(s): 木村元子、那須亮、三田恭義、中山俊憲
  • Organizer: 第２３回日本がん免疫学会総会
• [Presentation] CD69 regulates residency time of developing thymocytes that is important for NKT2 cell differentiation in the thymus (2019)
  • Author(s): Kimura M.Y., Hayashizaki, K., Yagi, R., Endo, Y., Motohashi, S. and Nakayama, T.
  • Organizer: EMBO Workshop ThymE: T cell and Thymus biology
  • Int'l Joint Research
• [Presentation] CD69 regulates T cell exhaustion at the tumor microenvironment (2019)
  • Author(s): Kimura M.Y.
  • Organizer: 3rd Annual CU-UCSD cMAV Symposium, UC San Diego, San Diego
  • Int'l Joint Research / Invited
• [Presentation] The role of CD69 on iNKT cell development in the thymus (2018)
  • Author(s): Kimura M.Y., Igi, A., Hayashizaki K., Mita Y., Endo, Y., Ogawa, S., Singer, A. and Nakayama, T.
  • Organizer: KAI International Meeting 2018, Sejong University Convention Center, Seoul, Korea
  • Int'l Joint Research / Invited
• [Presentation] CD69 regulates T-cell exhaustionin the tumor microenvironment (2018)
  • Author(s): Kimura M.Y., Mita Y. and Nakayama, T.
  • Organizer: Pusan National University, Busan, Korea
  • Invited
• [Presentation] The role of CD69 on iNKT cell development in the thymus (2018)
  • Author(s): Kimura M.Y.
  • Organizer: 2018 NIH Thymus symposium, Bethesda, USA
  • Int'l Joint Research / Invited
• [Presentation] CD69-Myl9 system regulates pathogenesis of inflammatory disorders (2018)
  • Author(s): Kimura M.Y., Hayashizaki K. and Nakayama T.
  • Organizer: The 2nd Chiba University-UC San Diego Symposium "Mucosal Immunology, Allergy and Vaccine"
  • Int'l Joint Research / Invited
• [Presentation] Role of CD69 on iNKT cell development in the thymus (2018)
  • Author(s): Kimura M.Y., Hayashizaki, K., Yagi, R., Endo, Y., Motohashi, S. and Nakayama, T.
  • Organizer: The 47th Annual Meeting of The Japanese Society for Immunology
• [Presentation] CD69による抗腫瘍免疫制御 (2018)
  • Author(s): 三田恭義、木村元子、那須亮、本橋新一郎、岡本美孝、中山俊憲
  • Organizer: 第７７回日本癌学会学術総会
• [Presentation] CD69による抗腫瘍免疫制御 (2018)
  • Author(s): 三田恭義、木村元子、那須亮、本橋新一郎、岡本美孝、中山俊憲
  • Organizer: 第２２回日本がん免疫学会総会
• [Presentation] 胸腺内細胞分化におけるCD69の重要性 (2018)
  • Author(s): 木村元子、伊木明美、林崎浩史、遠藤将大、中山俊憲
  • Organizer: 第83回日本インターフェロン・サイトカイン学術集会 (大会長特別枠講演)
• [Presentation] 胸腺内細胞分化におけるCD69の重要性 (2018)
  • Author(s): 木村元子
  • Organizer: Kyoto T Cell Conference 第28回学術集会
• [Remarks] 千葉大学大学院医学研究院免疫発生学
  • URL: https://www.m.chiba-u.ac.jp/class/meneki/jisseki/index.html
• [Remarks] 千葉大学大学院医学研究院免疫発生学
  • URL: https://www.m.chiba-u.ac.jp/class/meneki/