Analysis of cancer microenvironment under the growth control by anti-tumor immune response

• Project/Area Number: 18K19483
• 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: Juntendo University
• Principal Investigator: TAKEDA Kazuyoshi 順天堂大学, 医学(系)研究科(研究院), 准教授 (80272821)
• 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: IL-23p19 / IL-23レセプター / 肺転移 / NK細胞 / IFN-γ / CD96 / CD8T細胞 / PD-1 / 抗PD-1抗体 / 抗TIGIT抗体 / 腫瘍免疫 / Mutanome解析 / Immunome解析 / 癌間質細胞

Outline of Final Research Achievements

Cancer microenvironment, including immune environment, are composed of various cells and deeply involved in the progression, regression, and metastasis of cancer. The purpose of this study is to elucidate the biological reactions in cancer tissues changing with the progression, regression, and metastasis of the cancer. And, the ultimate goal is to develop innovative treatments that lead to the rejection of cancer by clarifying the biological condition of cancer tissue. In this study, I have reported the following findings. 1)IL-23 produced in metastatic lungs augments lung metastasis by inhibition of IFN-γ-producing NK cell induction. 2) PD-1, TIGIT, and CD96, that inhibit the immune activity, were expressed on cytotoxic CD8 T cells in cancer tissues. And, strategical suppression of these molecule-mediate signals is an effective antitumor immunotherapy.

Academic Significance and Societal Importance of the Research Achievements

癌細胞と宿主細胞の網羅的遺伝子発現とクロストークの解析により、癌増殖と拒絶の場である癌組織内の総合的な生体反応を定量的かつ網羅的に明らかにする。これにより癌増殖の理解に新たな視点を与え、革新的な治療法の開発につながると考えられる。さらに、本申請研究に得られるマウス癌モデルでの網羅的遺伝子解析情報は、現在世界中で行われているヒトサンプルを用いた網羅的遺伝子解析の結果を理解する助けとなると伴に、より早く革新的な治療ターゲットを提言する手助けとなるものと期待される。

Research Products

• [Int'l Joint Research] QIMR Berghofer Medical Research Inst./University of Queensland(オーストラリア)
• [Journal Article] Phase II adjuvant cancer-specific vaccine therapy for esophageal cancer patients curatively resected after preoperative therapy with pathologically positive nodes; possible significance of tumor immune microenvironment in its clinical effects. (2020)
  • Author(s): Yasuda, T., Nishiki, K., Hiraki, Y., Kato, H., Iwama, M., Shiraishi, O., Yasuda, A., Shinkai, M., Kimura, Y., Sukegawa, Y., Chiba, Y., Imano, M., Takeda, T., Satou, T., Shiozaki, H., and Nakamura, Y.
  • Journal Title: Annals of Surgery Volume: -
  • Peer Reviewed
• [Journal Article] Inhibition of Importin β1 Augments the Anticancer Effect of Agonistic Anti-Death Receptor 5 Antibody in TRAIL-Resistant Tumor Cells (2020)
  • Author(s): Yuko Kojima, Takashi Nishina, Hiroyasu Nakano, Ko Okumura, Kazuyoshi Takeda
  • Journal Title: Molecular Cancer Therapeutics Volume: 19-5 Issue: 5 Pages: 1123-1133
  • DOI: 10.1158/1535-7163.mct-19-0597
  • Peer Reviewed / Open Access
• [Journal Article] CD96 is immune checkpoint that regulated CD8+ T-cell antitumor function. (2019)
  • Author(s): Mittal, D., Lepletier, A., Madore, J., Aguilera, A. R., Stannard, K., Blake, S. J., Whitehall, V. J. L., Liu, C., Bettington, M. L., Takeda, K, Long, G. V., Scolyer, R. A., Lan, R., Siemers, N., Korman, A., Teng, M. W. L., Johnston, R. J., Dougall, W. C., and Smyth, M. J.
  • Journal Title: Cancer Immunol. Res. Volume: 7 Issue: 4 Pages: 559-571
  • DOI: 10.1158/2326-6066.cir-18-0637
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Effect of oral consumption of Panax ginseng aqueous extract on natural killer cell cytotoxicity in human. (2019)
  • Author(s): Takeda, K., and Okumura, K.
  • Journal Title: Pers. Medi. Univers. Volume: 8 Pages: 20-26
  • DOI: 10.1016/j.pmu.2018.09.001
  • Peer Reviewed
• [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] Quantitative T-cell repertoire analysis of peripheral blood mononuclear cells from lung cancer patients following long-term cancer peptide vaccination (2018)
  • Author(s): Takeda Kazuyoshi、Kitaura Kazutaka、Suzuki Ryuji、Owada Yuki、Muto Satoshi、Okabe Naoyuki、Hasegawa Takeo、Osugi Jun、Hoshino Mika、Tsunoda Takuya、Okumura Ko、Suzuki Hiroyuki
  • Journal Title: Cancer Immunology, Immunotherapy Volume: 67 Issue: 6 Pages: 949-964
  • DOI: 10.1007/s00262-018-2152-x
  • Peer Reviewed
• [Journal Article] CD155 loss enhances tumor suppression via combined host and tumor-intrinsic mechanisms. (2018)
  • Author(s): Li, X. Y., Das, I., Lepletier, A., Addala, V., Bald, T., Stannard, K., Barkauskas, D, Liu, J., Aguilera A. R., Takeda, K., Braun, M., Nakamura, K., Jacquelin, S., Steven W. Lane, S. W., Teng, M. W. L., Dougal, W. C., and Smyth, M. J.
  • Journal Title: J. CIin. Invest. Volume: 128 Issue: 6 Pages: 2613-2625
  • DOI: 10.1172/jci98769
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Experimental lung metastases in mice are more effectively inhibited by blockade of IL-23R than IL-23. (2018)
  • Author(s): Yan, J., Allen, S., Vijayan, D., Li, X. Y., Harjunpaa, H., Takeda, K., Liu, J., Cua, D. J., Smyth, M. J., and Teng, M. W. L.
  • Journal Title: Cancer Immunol. Res. Volume: 6 Issue: 8 Pages: 978-987
  • DOI: 10.1158/2326-6066.cir-18-0011
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Mobilization and Fcg-Receptor Expression of Six Cell Subsets, During and After Acute Exercise. American College of Sports Medicine (2019)
  • Author(s): 鈴井正敏、竹田和由、Shek, P. N.、Shephard, R. J.、奥村康
  • Organizer: American College of Sports Medicine the 66th Annual Meeting
  • Int'l Joint Research
• [Presentation] CAF-induced partial epithelial-mesenchymal transition mediated formation of metastatic human breast cancer clusters. (2019)
  • Author(s): 折茂彰、伊藤恭彦、目澤義弘、醍醐弥太郎、樋野興夫、竹田和由、浜田道昭、松村優子
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Importin β1 inhibition augments anticancer effect of anti-DR5 agonistic antibody in TRAIL resistant tumor cells. (2019)
  • Author(s): 小島裕子、仁科隆史、中野裕康、奧村康、竹田和由
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] 大腸癌モデルにおいてL.bulgaricus OLL1073R-1の菌体外多糖がもたらすCTLA-4阻害治療の効果増強と腫瘍浸潤T細胞解析 (2018)
  • Author(s): 川鍋（松田）啓誠、中村真梨枝、竹田和由、狩野宏、奥村康
  • Organizer: 第32回日本がん免疫学会総会
• [Presentation] CAFs induce formation of metastatic human breast tumor cell clusters with partial epithelial-mesenchymal transition (2018)
  • Author(s): 折茂彰、伊藤恭彦、目澤義弘、Kaidiliavi Sulidan、醍醐弥太郎、Nadia Wali、樋野興夫、竹田和由、浜田道昭、松村優子
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Activation of Src signaling mediates carcinoma-associated fibroblast-promoted metastasis in human breast cancers (2018)
  • Author(s): 伊藤恭彦、松村優子、目澤義弘、ソリタン カディア、ワリ ナディラ、寺尾保久、竹田省、奥村康、竹田和由、樋野興夫、折茂彰
  • Organizer: 第77回日本癌学会学術総会