Analysis of cancer immunceditine in antigen presentation-related molecules and development of treatment to inhibit escape mechanisms of cancer

• Project/Area Number: 18591534
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Thoracic surgery
• Research Institution: Mie University
• Principal Investigator: IKEDA Hiroaki Mie University, Department of Cancer Vaccine, Associate professor (40374673)
• Co-Investigator(Kenkyū-buntansha): 西村 孝司 北海道大学, 遺伝子病制御研究所, 教授 (30143001) ; 近藤 哲 北海道大学, 医学(系)研究科(研究院), 教授 (30215454) ; 宮本 正樹 北海道大学, 北海道大学病院, 助手 (40333611)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥3,860,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥360,000); Fiscal Year 2007: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2006: ¥2,300,000 (Direct Cost: ¥2,300,000)
• Keywords: Oncology / Immunology / Immunosurveillance / Immunoediting / Antigen presentation / Antigen epitope / Reeulatory T cells / GITR / 呼吸器外科学 / 消化器外科学

Research Abstract

(1) Research on human samples
Using tumor samples from esophageal cancer patients, we found that down-regulation of MHC class I in cancer cells negatively correlated with the infiltration of CD8^+ T cells in cancer tissues and infiltration of CD8^+ T cells in cancer tissues positively correlated with favorable patients' prognosis. These data suggest that CD8^+ T. cells play an important role in immunosurveillance against esophageal cancer and down-regulation of MHC class I can be a mechanism that esophageal cancer cells utilize to escape from immunosurveillance (manuscript in communication).
By analyzing 157 lung cancer samples, we found that infiltration of both CDC and CD8^+ T cells in tumor tissue correlated with favorable patients' prognosis. Moreover, tumor expression of MAGE-A4 in advanced lung cancer patients predicted short survival(Int J Oncol, 2006).
We engineered T cells to express a chimeric receptor consists of intracellular portion of T cell receptor and antibody against CEA . These genetically engineered cells were found to eradicate CEA-expressing autologous colon cancer cells efficiently(Cancer Sci, 2006).
We identified promiscuous peptides that can be recognized by NY-ESO-1 specific CD4^+ T cells(Cancer Sci, 2006).
We identified CLUAP1 as an Osteosarcoma-related tumor antigen(Int J Oncol, 2007).
(2) Research on mouse models
We found an importance of the interaction between antigen presenting cells and type I helper T cells in anti-tumor immune responses(Cancer Res, 2006). We also found an important role of type I interferon in cancer vaccine with a toll-like receptor ligand CpG(Int Immunol, 2006).
Utilizing tumor antigen-specific TCR transgenic mouse system, we found that tumor progression associated with increased regulatory T cells(Treg) limits the efficacy of adoptive cell therapy with tumor-specific CD8^+ T cells. Stimulation through co-stimulatory receptor GITR reduced Treg and induced effective T cell therapy even in the hosts with progressing tumors(SFCI 2007, CRI symposium in NY 2007, JCA 2007, JSI 2007). These results suggest that the maneuvers to stimulate co-stimulatory receptors such as GITR can be an efficient strategy to inhibit the mechanism of tumor to escape from immunosurveillance leading to an effective immunotherapy

Research Products

• [Journal Article] Identification of CLUAP1 as a human osteosarcoma tumor-associated antigen recognized by the humoral immune system. (2007)
  • Author(s): Ishikura H, Ikeda H, Abe H, Ohkuri T, Hiraga H, Isu K, Tsukahara T, Sato N, Minami A, Nishimura T
  • Journal Title: International Journal of Oncology 30 Pages: 461-467
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Identification of anovel NY-ESO-1 promiscuous helper epitope presented by multiple MHC class II molecules found frequently in the Japanese population (2007)
  • Author(s): Ohkuri T, Sato M, Abe H, Tsuji K, Yamagishi Y, Ikeda H, Matsubara N, Kitamura H, Nishimura T.
  • Journal Title: Cancer Science 98 Pages: 1092-1098
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Identification of CLUAP1 as a human osteosarcoma tumor-associated antigen recognized by the humoral immune system (2007)
  • Author(s): Ishikura, H, Ikeda, H, Abe, H, Ohkuri, T, Hiraga, H, Isu, K, Tsukahara, T, Sato, N, Minami, A, Nishimura, T
  • Journal Title: International Journal of Oncology 30 Pages: 461-467
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of a novel NY-ESO-1 promiscuous helper epitope presented by multiple MHC class II molecules found frequently in the Japanese population (2007)
  • Author(s): Ohkuri, T, Sato, M, Abe, H, Tsuji, K, Yamagishi, Y, Ikeda, H, Matsubara, N, Kitamura, H, Nishimura, T
  • Journal Title: Cancer Science 98 Pages: 1092-1098
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of a novel NY-ESO-1 promiscuous helper epitope presented by multiple MHC class II molecules found frequently in the Japanese population (2007)
  • Author(s): Ohkuri T, Sato M, Abe H, Tsuji K, Yamagishi Y, Ikeda H, Matsubara N, Kitamura H, Nishimura T.
  • Journal Title: Cancer Science 98 Pages: 1092-1098
  • Peer Reviewed
• [Journal Article] An essential role of antigen-presenting cell/T-helper type 1 cell-cell interactions in draining lymph node during complete eradication of class II-negative tumor tissue by T-helper type 1 cell therapy. (2006)
  • Author(s): Chamoto K, Wakita D, Narita Y, Zhang Y, Noguchi D, Ohnishi H, Iguchi T, Sakai T, Ikeda H, Nishimura T
  • Journal Title: Cancer Research 66 Pages: 1809-1817
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Expression of the MAGE-A4 and NY-ESO-1 cancer-testis antigens and T cell infiltration in non-small cell lung carcinoma and their prognostic significance. (2006)
  • Author(s): Yoshida N, Abe H, Ohkuri T, Wakita D, Sato M, Noguchi D, Miyamoto M, Morikawa T, Kondo S, Ikeda H Nishimura T
  • Journal Title: International Journal of Oncology 28 Pages: 1089-1098
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Antitumor activity of chimeric immunoreceptor gene-modified Tcl and Thl cells against autologous carcinoembryonic antigen-expressing colon cancer cells. (2006)
  • Author(s): Sasaki T, Ikeda, H, Sato M, Ohkuri T, Abe H, kuroki M, Onodera M, Miyamoto M, Kondo S, Nishimura, T
  • Journal Title: Cancer Science 97 Pages: 920-927
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] An indispensable role of type-1 IFNs for inducing CTL-mediated complete eradication of established tumor tissue by CpG-liposome co-encapsulated with model tumor antigen. (2006)
  • Author(s): Wakita D, Chamoto K, Zhang Y, Narita Y, Noguchi D, Ohnishi H, Iguchi T, Sakai T, Ikeda H, Nishimura T
  • Journal Title: International Immunology 18 Pages: 425-434
  • NAID: 10020620780
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] lalpha, 25-Dihydroxyvitamin D3 downmodulates the functional differentiation of Th1 cytokine-conditioned bone marrow-derived dendritic cells beneficial for cytotoxic T lymphocyte generation. (2006)
  • Author(s): Matsuzaki J, Tsuii T, Zhang Y, Wakita D, Imazeki I, Sakai T, Ikeda H, Nishimura T
  • Journal Title: Cancer Science 97 Pages: 139-147
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] An essential role of. antigen-presenting cell/T-helper type 1 cell-cell interactions in draining lymph node during complete eradication of class II-negative tumor tissue by T-helper type 1 cell therapy (2006)
  • Author(s): Chamoto, K, Wakita, D, Narita, Y, Zhang, Y, Noguchi, D, Ohnishi, H, Iguchi, T, Sakai, T, Ikeda, H, Nishimura, T
  • Journal Title: Cancer Research 66 Pages: 1809-1817
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Expression of the MAGE-A4 and NY-ESO-1 cancer-testis antigens and T cell infiltration in non-small cell lung carcinoma and their prognostic significance (2006)
  • Author(s): Yoshida, N, Abe, H, Ohkuri, T, Wakita, D, Sato, M, Noguchi, D, Miyamoto, M, Morikawa, T, Kondo, S, Ikeda, H, Nishimura, T
  • Journal Title: International Journal of Oncology 28 Pages: 1089-1098
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Antitumor activity of chimeric immunoreceptor gene-modified Tc1 and Th1 cells against autologous carcinoembryonic antigen-expressing colon cancer cells (2006)
  • Author(s): Sasaki, T, Ikeda, H, Sato, M, Ohkuri, T, Abe, H, Kuroki, M, Onodera, M, Miyamoto, M, Kondo, S, Nishimura, T
  • Journal Title: Cancer Science 97 Pages: 920-927
  • NAID: 10018767677
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] An indispensable role of type-1 IFNs for inducing CTL-mediated complete eradication of established tumor tissue by CpG-liposome co-encapsulated with model tumor antigen (2006)
  • Author(s): Wakita, D, Chamoto, K, Zhang, Y, Narita, Y, Noguchi, D, Ohnishi, H, Iguchi, T, Sakai, T, Ikeda, H, Nishimura, T
  • Journal Title: International Immunology 18 Pages: 425-434
  • NAID: 10020620780
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] lalpha,25-Dihydroxyvitamin D3 downmodulates the functional differentiation of Th1 cytokine-conditioned bone marrow-derived dendritic cells beneficial for cytotoxic T lymphocyte generation (2006)
  • Author(s): Matsuzaki, J, Tsuji, T, Zhang, Y, Wakita, D, Imazeki, I, Sakai, T, Ikeda, H, Nishimura, T
  • Journal Title: Cancer Science 97 Pages: 139-147
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] An essential role of antigen-presenting cell/T-helper type 1 cell-cell interactions in draining Iymph node during complete eradication of class II-negative tumor tissue by T-helper type 1 cell therapy. (2006)
  • Author(s): Chamoto K, Wakita D, Narita Y, Zhang Y, Noguchi D, Ohnishi H, Iguchi T, Sakai T, Ikeda H, Nishimura T
  • Journal Title: Cancer Research 66 Pages: 1809-1817
• [Journal Article] Antitumor activity of chimeric immunoreceptor gene-modified Tcl and Thl cells against autologous carcinoembryonic antigen-expressing coloncancer cells. (2006)
  • Author(s): Sasaki T, Ikeda, H, Sato M, Ohkuri T, Abe H, Kuroki M, Onodera M, Miyamoto M, Kondo S, Nishimura, T
  • Journal Title: Cancer Science 97 Pages: 920-927
• [Journal Article] lalpha, 25-Dihydroxyvitamin D3 downmodulates the functional differentiation of Thl cytokine-conditioned bone marrow-derived dendritic cells beneficial for cytotoxic T lymphocyte generation. (2006)
  • Author(s): Matsuzaki J, Tsuji T, Zhang Y, Wakita D, Imazeki I, Sakai T, Ikeda H, Nishimura T
  • Journal Title: Cancer Science 97 Pages: 139-147
• [Presentation] GITR stimulation enhances anti-tumor effect of adoptive cell therapy restoring activation of antigen-specific CD8^+ T cells (2007)
  • Author(s): Ikeda H, Imai N, Nishikawa N, Kato T, Tawara I, Mori K, Wang L, Shiku H.
  • Organizer: 第37回日本免疫学会総会・学術集会
  • Place of Presentation: 東京
  • Year and Date: 2007-11-22
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] GITR stimulation enhances anti-tumor effect of adoptive cell therapy restoring activation of antigen-specific CD8^+ T cells (2007)
  • Author(s): Ikeda, H, Imai, N, Nishikawa, N, Kato, T, Tawara, I, Mori, K, Wang, L, Shiku, H
  • Organizer: 37th Annual Meeting of JSI
  • Place of Presentation: Tokyo
  • Year and Date: 2007-11-22
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] GITR stimulation enhances antitumor effect of adoptive cell therapy restoring activation of antigenspecific CD8+ T cells (2007)
  • Author(s): Ikeda H, Imai N, Nishikawa N, Kato T, Tawara I, Mori K, Wa ngL, Shiku H.
  • Organizer: 第37回日本免疫学会総会・学術集会
  • Place of Presentation: 東京
  • Year and Date: 2007-11-22
• [Presentation] GITR stimulation enhances anti-tumor effect of adoptive cell therapy with antigen-specific CD8^+ T cells (2007)
  • Author(s): Nishikawa N, Imai N, Ikeda H, Kato T, Tawara I, Mori K, Wang L, Shiku H.
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-05
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] GITR stimulation enhances anti-tumor effect of adoptive cell therapy with antigen-specific CD8^+ T cells (2007)
  • Author(s): Nishikawa, N, Imai, N, Ikeda, H, Kato, T, Tawara, I, Mod, K, Wang, L, Shiku, H
  • Organizer: 66th, Annual meeting of JCA
  • Place of Presentation: Yokohama
  • Year and Date: 2007-10-05
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] GITR stimulation enhances anti-tumor effect of adoptive cell therapy with antigen-specific CD8+ T cells (2007)
  • Author(s): Nishikawa N, Imai N, Ikeda H, Kato T, Tawara I, Mori K, Wang L, Shiku H.
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-05
• [Presentation] GITR stimulation enhances anti-tumor effect of adoptive cell therapy restoring activation of antigen-specific CD8^+ T cells (2007)
  • Author(s): Imai N, Ikeda H, Nishikawa H, Yamashita Y, Tawara I, Kato T Shiku H.
  • Organizer: Cancer Research Institute, International Cancer Immunotherapy Symposia Series
  • Place of Presentation: 米国ニューヨーク
  • Year and Date: 2007-10-04
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] A clinical trial of CHP-HER2 vaccine with adjuvant GM-CSF: A case representing antigen spreading (2007)
  • Author(s): Kitano S, Kageyama S, Nishikawa H, Hirayama M, Hiasa A, Ikeda, H, Old, LJ, Shiku H.
  • Organizer: Cancer Research Institute, International Cancer Immunotherapy Symposia Series
  • Place of Presentation: 米国ニューヨーク
  • Year and Date: 2007-10-04
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] stimulation enhances anti-tumor effect of adoptive cell therapy restoring activation of antigen-specific CDS^+ T cells (2007)
  • Author(s): Imai, N, Ikeda, H, Nishikawa, H, Yamashita, Y, Tawara, I, Kato, T, Shiku, H. GITR
  • Organizer: Cancer Research Institute, International Cancer Immunotherapy Symposia Series
  • Place of Presentation: NY
  • Year and Date: 2007-10-04
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] A clinical trial of CHIP-HER2 vaccine with adjuvant GM-CSF : A case representing antigen spreading (2007)
  • Author(s): Kitano, S, Kageyama, S, Nishikawa, H, Hirayama, M, Hiasa, A, Ikeda, H, Old, IJ, Shiku, H
  • Organizer: Cancer Research Institute, International Cancer Immunotherapy Symposia Series
  • Place of Presentation: NY
  • Year and Date: 2007-10-04
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] GITR stimulation enhances antitumor effect of adoptive cell therapy restoring activation of antigen・specfic CD8+ T cells (2007)
  • Author(s): Imai N, Ikeda H, Nishikawa H, Yamashita Y, Tawara I, Kato T, Shiku H.
  • Organizer: Cancer Research Institute, International Cancer Immunotherapy Symposia Series
  • Place of Presentation: 米国ニューヨーク
  • Year and Date: 2007-10-04
• [Presentation] A clinical trial of CHP・HER2 vaccine with adjuvant GM-CSF: A case representing antigen spreading (2007)
  • Author(s): Kitano S, Kageyama S, Nishikawa H, Hirayama M, Hiasa A, Ikeda, H, Old, LJ, Shiku H.
  • Organizer: Cancer Research Institute, International Cancer Immunotherapy Symposia Series
  • Place of Presentation: 米国ニューヨーク
  • Year and Date: 2007-10-04
• [Presentation] 腫瘍特異的CD8^+T細胞移入療法のGITR刺激による効果増強機序の解析 (2007)
  • Author(s): 今井奈緒子、池田裕明、西川博嘉、加藤琢磨、俵功、森和子、王立楠、珠玖洋
  • Organizer: 第11回基盤的癌免疫研究会総会
  • Place of Presentation: 東京
  • Year and Date: 2007-07-12
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Mechanism of GITR-mediated enhancement of adoptive cell therapy of tumor-specific CD8^+ T cells (2007)
  • Author(s): Imai, N, Ikeda, H, Nishikawa, H, Kato, T, Tawara, I, Mod, K, Wang, L, Shiku, H
  • Organizer: 11th Annual Meeting of SFCI
  • Place of Presentation: Tokyo
  • Year and Date: 2007-07-12
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] 腫瘍特異的CD8+T細胞移入療法のGITR刺激による効果増強機序の解析 (2007)
  • Author(s): 今井 奈緒子、池田 裕明、西川 博嘉、加藤 琢磨、俵功、森 和子、王 立楠、珠玖 洋
  • Organizer: 第11回基盤的癌免疫研究会総会
  • Place of Presentation: 東京
  • Year and Date: 2007-07-12
• [Presentation] T細胞免疫反応と免疫記憶Homeostatic Prolferationで誘導されるEm、Cmの性状解析と自己免疫病との関連性 (2006)
  • Author(s): 野口大輔, 脇田大功, 小坂朱, 成田義規, 大西英晃, 松原直紀, 北村秀光, 池田裕明, 西村孝司
  • Organizer: 第36回本免疫学会総会・学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2006-12-11
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Analysis of Em and Cm cells induced by homeostatic proliferation and its relationship to autoimmune disease (2006)
  • Author(s): Noguchi, D, Wakita, D, Kosaka, A, Narita, Y, Ohnishi, H, Matsubara, N, Kitamura, H, Ikeda, H, Nishimura, T
  • Organizer: 36th Annual Meeting of JSI
  • Place of Presentation: Osaka
  • Year and Date: 2006-12-11
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Th1細胞治療に有用なNY-ESO-1及びMAGE-A4特異的Th細胞の誘導と新規ヘルパーエピトープの同定 (2006)
  • Author(s): 辻景子, 大栗敬幸, 阿部洋行, 佐藤政芳, 池田裕明, 松原直紀, 富樫裕二, 北村秀光, 西村孝司
  • Organizer: 第65回日本癌学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2006-09-29
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Identification of new helper epitope of NY-ESO-1 and MAGE-A4 for efficient Th1 cell therapy (2006)
  • Author(s): Tsuji, K, Ohkuri, T, Abe, H, Sato, M, Ikeda, H, Matsubara, N, Togashi, Y, Kitamura, H, Nishimura, T
  • Organizer: 65th, Annual Meeting of JCA
  • Place of Presentation: Yokohama
  • Year and Date: 2006-09-29
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] NY-ESO-1および,MAGE-A4特異的Th細胞の誘導と,新規ヘルパーエピトープの同定 (2006)
  • Author(s): 大栗敬幸, 辻景子, 阿部洋行, 佐藤政芳, 山岸結香, 池田裕明, 松原直紀, 冨樫裕二, 北村秀光, 西村孝司
  • Organizer: 第10回基盤的癌免疫研究会総会
  • Place of Presentation: 札幌
  • Year and Date: 2006-07-14
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Identification of new helper epitope of NY-ESO-1 and MAGE-A4 by induction of specific helper T cells (2006)
  • Author(s): Ohkuri, T, Tsuji, K, Abe, H, Sato, M, Yamagishi, Y, Ikeda, H, Matsubara, N, Togashi, Y, Kitamura, H, Nishimura, T
  • Organizer: 10th Annual Meeting of SFCI
  • Place of Presentation: Sapporo
  • Year and Date: 2006-07-14
  • Description: 「研究成果報告書概要(欧文)」より
• [Remarks] 「研究成果報告書概要(和文)」より
  • URL: http://www.medic.mie-u.ac.jp/cancervac/index.html
• [Remarks]
  • URL: http://www.medic.mie-u.ac.jp/cancervac/index.html