Analysis of molecular mechanisms underlying acquired resistance of tumor cells responding to anti-tumor immunity

• Project/Area Number: 18H02695
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• 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): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2020: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2019: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2018: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 抗腫瘍免疫 / 免疫抵抗性 / CD155 / TRAIL/DR5 / Importin β1 / 骨転移 / 炎症 / 骨芽細胞 / 破骨細胞 / TSLP / RANKL / 耐性変異 / TRAIL / DR5 / 抗DR5抗体 / 免疫耐性変異 / PD-L1/PD-1

Outline of Final Research Achievements

Biological characters of cancer cells are altered responding to host responses including immune responses, and this is the essential mechanism by which cancer cells acquire resistance against various therapies. The purpose of this study is to elucidate the mechanisms that induce adaptive immune resistance by immune responses, and I have reported the following findings.
1) CD155 expressed on cancer cells and/or myeloid cells plays important role to escape anti-tumor immune responses. 2) Augmentation of DR5 surface expression overcomes the resistance against cell-death inducing cancer therapy. 3) TSLP produced by osteoblasts in inflamed micro metastasis would play roles for bone metastasis formation.

Academic Significance and Societal Importance of the Research Achievements

癌特異的免疫反応に応答して起きる癌細胞自体の変化こそが、癌細胞が治療抵抗性となる本質的機序であり、この克服なしには治療効果には限界がある。すなわち、発癌、増殖、転移の過程における癌細胞の形質転換が癌細胞の治療抵抗性獲得の原因であることが示されている。本研究により、癌増殖過程での新たな免疫抑制分子の発現や細胞死抵抗性の新規獲得、さらには骨転移初期の炎症惹起による骨代謝制御が起きていることが示され、これらの克服が免疫療法を含む癌治療法の奏功率の向上に繋がることが示された。

Research Products

• [Int'l Joint Research] QIMR Berghofer Medical Research Inst.(オーストラリア)
• [Int'l Joint Research] Institut Pasteur(フランス)
• [Int'l Joint Research] QIMR Berghofer Medical Research Inst./University of Queensland(オーストラリア)
• [Journal Article] Anti-CD321 antibody immunotherapy protects liver against ischemia and reperfusion-induced injury. (2021)
  • Author(s): Enzhi Yin, Takeshi Fukuhara, Kazuyoshi Takeda, Yuko Kojima, Kyoko Fukuhara, Kenichi Ikejima, Hisashi Bashuda, Jiro Kitaura, Hideo Yagita, Ko Okumura, Koichiro Uchida
  • Journal Title: Scientific Reports Volume: 6322 Issue: 1 Pages: 1-10
  • DOI: 10.1038/s41598-021-85001-2
  • Peer Reviewed / Open Access
• [Journal Article] TSLP is a negative regulator of RANKL-induced osteoclastogenesis. (2020)
  • Author(s): Ohno, T., Nakamura, T., Nakae, S., Morita, H., Matsumoto, K., Takeda, K., Okumura, K., and Azuma, T.
  • Journal Title: Biochem. Biophsy. Res. Commun. Volume: 530 Issue: 3 Pages: 508-512
  • DOI: 10.1016/j.bbrc.2020.05.055
  • Peer Reviewed
• [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, K., Satou, T., Shiozaki, H., and Nakamura, Y.
  • Journal Title: Ann. Surg. Volume: 2020 Issue: 1 Pages: e155-e162
  • DOI: 10.1097/sla.0000000000003880
  • Peer Reviewed
• [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] Phase II adjuvant peptide vaccine for postoperative esophageal cancer patients with pathologically positive nodes (2020)
  • Author(s): 安田卓司、錦耕平、平木洋子、加藤寛章、白石治、安田篤、新海政幸、木村豊、助川寧、千葉康敬 、今野元博、竹田和由、佐藤隆夫、塩崎均、中村祐輔
  • Organizer: 第79回日本癌学会学術集会
• [Presentation] Mobilization and Fcγ-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: 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