がん微小環境により癌が免疫耐性を新規に獲得する機構の解析

• Project Area: Integrative Research on Cancer Microenvironment Network
• Project/Area Number: 23112519
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Juntendo University
• Principal Investigator: 竹田 和由 順天堂大学, 医学部, 准教授 (80272821)
• Project Period (FY): 2011-04-01 – 2013-03-31
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000); Fiscal Year 2012: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2011: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
• Keywords: がん微小環境 / 免疫 / 炎症 / 遺伝子変異 / 抗原性 / CTL / NK細胞 / 樹状細胞 / MHC Class II / tropocytosis / CD4 T細胞 / 免疫抑制

Outline of Annual Research Achievements

本研究の目的は、がん微小環境および癌組織内の免疫反応とのクロストークにより、癌細胞が免疫耐性を獲得する新規の変異を起こす分子機構を解明することである。これまでに、固形癌中のNK細胞は樹状細胞との接触により樹状細胞表面のMHC Class IIを奪取しMHC Class II-dressed NK細胞となり、樹状細胞によるCD4 T細胞の活性化を競合的に抑制し、T細胞依存的免疫反応を抑制するフィードバック効果を発揮している可能性を示唆した。また、癌塊内に浸潤した腫瘍特異的 CTLは特異的に CD137(4.1BB)を発現することを見出し、アゴニステック抗CD137抗体の養子免疫療法（CTL移入療法）との併用は副作用無く特異的に抗腫瘍効果を増強することを報告した。従って、本来の目的に付随した癌塊内の特異的免疫環境の一端に関しては、これを明らかにし報告することができた。
残念ながら本来の研究目的に関しては年度内に発表することができなかった。しかし、免疫不全マウスとwild-typeマウスで増殖している癌細胞の遺伝子発現の比較検討、異なったいくつかの遺伝子操作マウスで増殖した抗原性の高い遺伝子を導入した同一の癌細胞間での遺伝子発現および同条件で増殖した親株との遺伝子発現の比較を行ってきた。その結果、生体内のがん微小環境に依存して、腫瘍抗原特異的な免疫反応への応答により癌細胞内で遺伝子の変化が誘導され抗原性が低下した癌細胞が出現するという、癌細胞が発癌時または抗腫瘍免疫治療時にがん微小環境において免疫反応をエスケープする機構の一端を解明することができたと考えており、現在論文作成中である。

Research Progress Status

24年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

24年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Phase I clinical trial of a peptide vaccine combinated with tegafur-uracil plus leucovorin for treatment of advanced or recurrent colorectal cancer (2013)
  • Author(s): Matsusita N, Aruga A, Inoue Y, Kotera Y, Takeda K, Yamamoto M
  • Journal Title: Oncol. Rep Volume: 29 (3) Issue: 3 Pages: 951-959
  • DOI: 10.3892/or.2013.2231
  • Peer Reviewed
• [Journal Article] Cancer peptide vaccine therapy developed from oncoantigens identified through genome-wide expression profile analysis for bladder cancer (2012)
  • Author(s): Obara W, Ohsawa R, Kanehira M, 他全10名
  • Journal Title: Jpn. J. Clin. Oncol Volume: 42 (7) Issue: 7 Pages: 591-600
  • DOI: 10.1093/jjco/hys069
  • Peer Reviewed
• [Journal Article] Targeting spatiotemporal expression of CD137 on tumor-infiltrating cytotoxic T lymphocytes as a novel strategy for agonistic antibody therapy. (2012)
  • Author(s): Noji S, Hosoi A, Takeda K, Matsushita H, Morishita Y, Seto Y, Kakimi K.
  • Journal Title: J. Immunother Volume: 35(6) Issue: 6 Pages: 460-472
  • DOI: 10.1097/cji.0b013e31826092db
  • Peer Reviewed
• [Journal Article] Beta-glucosylceramide administration (i.p.) activates natural killer T cells in vivo and prevents tumor metastasis in mice. (2012)
  • Author(s): Inafuku, M.
  • Journal Title: Lipids Volume: 47 Issue: 6 Pages: 581-591
  • DOI: 10.1007/s11745-012-3666-1
  • Peer Reviewed
• [Journal Article] Significant clinical response of advanced colon cancer to peptide vaccine therapy: a case report. (2012)
  • Author(s): Yasuda, S.
  • Journal Title: Tokai J. Exp. Clin. Med. Volume: 37 Pages: 57-61
  • Peer Reviewed
• [Journal Article] Multicenter, phase II clinical trial of cancer vaccination for advanced esophageal cancer with three peptides derived from novel cancer-testis antigens. (2012)
  • Author(s): Kono K
  • Journal Title: J Transl Med Volume: 10（141） Issue: 1 Pages: 141-141
  • DOI: 10.1186/1479-5876-10-141
  • Peer Reviewed
• [Journal Article] Identification of HLA-A24-restricted novel T cell epitope peptide derived from P-cadherin and kinesin family member 20A (2012)
  • Author(s): Osawa R, Tsunoda T, Yoshimura S, 他全10名
  • Journal Title: J. Biomed. Biotech Volume: 2012 Pages: 848042-848042
  • DOI: 10.1155/2012/848042
  • Peer Reviewed
• [Journal Article] Phase I/II study of S-1 plus cisplatin combined with peptide vaccines for human vascular endothelial growth factor receptor 1 and 2 in patients with advanced gastric cancer (2012)
  • Author(s): Masuzawa T, Fujiwara Y, Okada K, 他全16名中
  • Journal Title: Int. J. Oncol Volume: 41 (4) Issue: 4 Pages: 1297-1304
  • DOI: 10.3892/ijo.2012.1573
  • Peer Reviewed
• [Journal Article] Tumor necrosis factor receptor-associated factor (TRAF) 2 control homeostasis of the colon to prevent spontaneous development of murine inflammatory bowel disease (2011)
  • Author(s): Piao, J.H., Hasegawa, M., et al
  • Journal Title: J.Biol.Chem. Volume: 286 Issue: 20 Pages: 17879-17888
  • DOI: 10.1074/jbc.m111.221853
  • Peer Reviewed
• [Journal Article] CD1d-restricted natural killer T cells contribute to hepatic inflammation and fibrogenesis in mice (2011)
  • Author(s): Ishikawa, S., Ikejima, K., et al
  • Journal Title: J.Hepatol. Volume: 54 Issue: 6 Pages: 1195-1204
  • DOI: 10.1016/j.jhep.2010.08.022
  • Peer Reviewed
• [Journal Article] IFN-γ production by lung NK cells is sritical for the natural resistance to pulumonary metastasis of B16 melanoma in mice (2011)
  • Author(s): Takeda, K., Nakayama, M., et al
  • Journal Title: J.Leukoc.Biol. Volume: 90 Issue: 4 Pages: 777-785
  • DOI: 10.1189/jlb.0411208
  • Peer Reviewed
• [Journal Article] Early activation and interferon-Y production of tumor-infiltrating mature CD27 high natural killer cells (2011)
  • Author(s): Y.Hayakawa
  • Journal Title: Cancer Sci Volume: 102 Issue: 11 Pages: 1967-1971
  • DOI: 10.1111/j.1349-7006.2011.02042.x
  • Peer Reviewed
• [Journal Article] Interaction between NK cells and dendritic cells generate MHC class II-dressed NK cells to regulate CD4^+ T cells (2011)
  • Author(s): Nakayama M, et al
  • Journal Title: Proc.Natl.Acad.Sci.USA Volume: 108 Issue: 45 Pages: 18360-18365
  • DOI: 10.1073/pnas.1110584108
  • Peer Reviewed
• [Journal Article] Importin β1 protein-mediated nuclear localization of death receptor 5 (DR5) limits DR5/tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced cell death of human tumor cells (2011)
  • Author(s): Kojima Y, Nakayama M, Nishina T, Nakano H, Koyanagi M, Takeda K, Okumura K, Yagita H
  • Journal Title: J Biol Chem Volume: 286 Issue: 50 Pages: 43383-43393
  • DOI: 10.1074/jbc.m111.309377
  • Peer Reviewed
• [Presentation] The discriminatory activation of tumor specific cytotoxic T lymphocytes localized in the tumor by anti-4-1 BB mAb (2011)
  • Author(s): 細井亮宏
  • Organizer: 日本免疫学会
  • Place of Presentation: 幕張メッセ
  • Year and Date: 2011-11-28
• [Presentation] NK-dendritic cell interactions generate MHC class II-dressed NK cells that regulate CD4+ T cells (2011)
  • Author(s): 中山勝文
  • Organizer: 日本免疫学会
  • Place of Presentation: 幕張メッセ
  • Year and Date: 2011-11-27