Potentiation of cancer immunotherapy using spatiotemporal regulation of heat shock protein-TLR ligand complex

• Project/Area Number: 23590427
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Sapporo Medical University
• Principal Investigator: MATSUZAKI Junichi 札幌医科大学, 医学部, 研究員 (80448597)
• Co-Investigator(Kenkyū-buntansha): TAMURA Yasuaki 北海道大学, 大学院先端生命科学研究院, 特任教授 (80322329)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2013: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2011: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: がんペプチドワクチン / 熱ショック蛋白質 / 自然免疫 / 細胞障害性T細胞 / クロスプレゼンテーション / 樹状細胞 / 抗原ペプチド / 免疫賦活剤 / Hsp90 / Hsp72 / TLR / 形質細胞様樹状細胞 / CpG / LPS / Toll様受容体 / 癌ワクチン

Research Abstract

We have demonstrated that Hsp90 can act as an efficient inducer for crosspresentation of associated antigenic peptide via spatiotemporal regulation. We examined whether vaccination with Hsp90-antigen peptide complex and TLR ligand augmented the induction of cytotoxic T cell (CTL) response via crosspresentation. Interestingly, plasmacytoid dendritic cells (pDCs) secreted not only IFN-a but also Hsp72 in response to CpG-A administration. We found that the secreted Hsp72 formed complex with Hsp90-peptide complex, leading to the efficient crosspresentation and CTL induction against associated peptide. These data suggest that CpG-A is a good candidate as an immunoadjuvant for Hsp90-based cancer vaccine.

Research Products

• [Journal Article] Expression of ECRG4 is associated with lower proliferative potential of esophageal cancer cells (2013)
  • Author(s): Matsuzaki J, Torigoe T, Hirohashi Y, Tamura Y, Asanuma H, Nakazawa E, Saka E, Yasuda K, Takahashi S, Sato N
  • Journal Title: Pathol Int. Volume: 63(8) Issue: 8 Pages: 391-7
  • DOI: 10.1111/pin.12079
  • Peer Reviewed
• [Journal Article] Six-transmembrane epithelial antigen of the prostate-1 plays a role for in vivo tumor growth via intercellular communication (2013)
  • Author(s): Yamamoto T, Tamura Y, Kobayashi J, Kamiguchi K, Hirohashi Y, Miyazaki A, Torigoe T, Asanuma H, Hiratsuka H, Sato N
  • Journal Title: Exp. Cell Res. Volume: 319 Issue: 17 Pages: 2617-29
  • DOI: 10.1016/j.yexcr.2013.07.025
  • Peer Reviewed
• [Journal Article] Preferential expression of cancer/testis genes in cancer stem-like cells : proposal of a novel sub-category, cancer/testis/stem gene. (2013)
  • Author(s): Yamada R, Takahashi A, Torigoe T, Morita R, Tamura Y, Tsukahara T, Kanaseki T, Kubo T, Watarai K, Kondo T, Hirohashi Y, Sato N.
  • Journal Title: Tissue Antigens. Volume: 81(6) Issue: 6 Pages: 428-34
  • DOI: 10.1111/tan.12113
  • Peer Reviewed
• [Journal Article] Human Endoplasmic Reticulum Oxidoreductin 1-α(hERO1-α) is a Novel Predictor for Poor Prognosis of Breast Cancer (2013)
  • Author(s): Kutomi G, Tamura Y, Tanaka T, Kajiwara T, Kukita K, Ohmura T, Shima H, Takamaru T, Satomi F, Suzuki Y, Torigoe T, Sato N, Hirata H
  • Journal Title: Cancer Sci. Volume: 104 Issue: 8 Pages: 1091-6
  • DOI: 10.1111/cas.12177
  • Peer Reviewed
• [Journal Article] Expression and function of FERMT genes in colon carcinoma cells (2013)
  • Author(s): Kiriyama, K., Hirohashi, Y., Torigoe, T., Kubo, T., Tamura, Y., Kanaseki, T., Takahashi, A., Nakazawa, E., Saka, E., Ragnarsson, C., Natatsugawa, M., Inoda, S., Asanima, H., Takasu, H., Hasegawa, T., Yasoshima, T, Hirata, K., Sato, N.
  • Journal Title: Anticancer Res. Volume: 33 Pages: 167-173
  • Peer Reviewed
• [Journal Article] Immunotherapeutic benefit ofα-interferon (IFNα) in survivin2B-derived peptide vaccination for advanced pancreatic cancer patients (2013)
  • Author(s): Kameshima H, Tsuruma T, Kutomi G, Shima H, Iwayama Y, Kimura Y, Imamura M, Torigoe T, Takahashi A, Hirohashi Y, Tamura Y, Tsukahara T, Kanaseki T, Sato N, Hirata K
  • Journal Title: Cancer Sci. Volume: 104 Issue: 1 Pages: 124-129
  • DOI: 10.1111/cas.12046
  • Peer Reviewed
• [Journal Article] DNA methyltransferase 1 is essential for initiation of the colon cancers (2013)
  • Author(s): Morita R,Hirohashi Y,Suzuki H, et al
  • Journal Title: Experimental and Molecular Pathology Volume: 94 Issue: 2 Pages: 322-329
  • DOI: 10.1016/j.yexmp.2012.10.004
  • Peer Reviewed
• [Journal Article] Highexpression of ALDH1 and SOX2 diffuse staining pattern of oral squamous cellcarcinomas correlates to lymph node metastasis. (2013)
  • Author(s): Michifuri Y, Hirohashi Y, Torigoe T,Miyazaki A, Kobayashi J, Sasaki T, FujinoJ, Asanuma H, Tamura Y, Nakamori K, Hasegawa T, Hiratsuka H, Sato N.
  • Journal Title: Pathol Int. Volume: 62(10) Issue: 10 Pages: 684-9
  • DOI: 10.1111/j.1440-1827.2012.02851.x
  • Peer Reviewed
• [Journal Article] Expression of ECRG4 is associated with lower proliferative potential of esophageal cancer cells. (2013)
  • Author(s): Matsuzaki J, Torigoe T, Hirohashi Y, Tamura Y, Asanuma H, Nakazawa E, Saka E, Yasuda K, Takahashi S, Sato N.
  • Journal Title: Pathology International Volume: 63 Pages: 391-397
  • Peer Reviewed
• [Journal Article] Heat-shock proteins as endogenous ligands building a bridge between innate and adaptive immunity. (2012)
  • Author(s): Tamura Y, Torigoe T, Kukita K, Saito K, Okuya K, Kutomi G, Hirata K, Sato N.
  • Journal Title: Immunotherapy Volume: 8 Issue: 8 Pages: 841-852
  • DOI: 10.2217/imt.12.75
  • Peer Reviewed
• [Journal Article] New paradigm for intrinsic function of heat shock proteins as endogenous ligands in inflammation and innate immunity (2012)
  • Author(s): Tamura Y, Torigoe T, Kutomi G, Hirata K, Sato N
  • Journal Title: Curr Mol Med Volume: 12 Pages: 1198-1206
  • Peer Reviewed
• [Journal Article] Heat shock enhances the expression of cytotoxic granule proteins and augments the activities of tumor-associated antigen-specific cytotoxic T lymphocytes (2012)
  • Author(s): Takahashi A, Torigoe T, Tamura Y, Kanaseki T, Tsukahara T, Sasaki Y, Kameshima H, Tsuruma T, Hirata K, Tokino T, Hirohashi Y, Sato N
  • Journal Title: Cell Stress Chaperones Volume: 17 Issue: 6 Pages: 757-763
  • DOI: 10.1007/s12192-012-0348-0
  • Peer Reviewed
• [Journal Article] N-propionyl-4-S-cysteaminylphenol induces apoptosis in B16F1cells and mediates tumor-specific T-cell immune responses in a mouse melanoma model. (2012)
  • Author(s): Ishii-Osai, Y.
  • Journal Title: J. Dermatol. Sci. Volume: 67 Issue: 1 Pages: 51-60
  • DOI: 10.1016/j.jdermsci.2012.04.009
  • Peer Reviewed
• [Journal Article] Heat shock protein 40 family, DNAJB8 is expressed in renal cancer stem-like cell, controls the tumor-initiating ability and can be a potent target of immunotherapy. (2012)
  • Author(s): Nishizawa, S., Mori, T., Hirohashi, Y., Torigoe, T., Tamura, Y., Kamiguchi, K., Takahashi, A., Kanaseki, T., Nakazawa, E., Asanuma, H., Sokolovskaya, A., Morita, R., Yamada, R., Fujii, R., Kondo, T., Hasegawa, T., Hara, I. and Sato, N.
  • Journal Title: Cancer Res Volume: (in press) Issue: 11 Pages: 2844-54
  • DOI: 10.1158/0008-5472.can-11-3062
  • Peer Reviewed
• [Journal Article] Establishment of a monoclonal anti-pan HLA class I antibody suitable for immunostaining of formalin-fixed tissue : Unusually high frequency of down-regulation in breast cancer tissues (2012)
  • Author(s): Torigoe, T., Asanuma, H., Nakazawa. E., Tamura, Y., Hirohashi, Y., Yamamoto, E., Kanaseki, T., Hasegawa, T., Sato, N.
  • Journal Title: Pathol Int Volume: 62 Issue: 5 Pages: 303-8
  • DOI: 10.1111/j.1440-1827.2012.02789.x
  • NAID: 10031185205
  • Peer Reviewed
• [Journal Article] ECRG4 is a negative regulator of caspase-8-mediated apoptosis in human T-leukemia cells (2012)
  • Author(s): Matsuzaki J,Torigoe T,Hirohashi Y, Kamiguchi K,Tamura Y, Tsukahara T,Kubo T, Takahashi A, Nakazawa E,Saka E, Yasuda K,Takahashi S,Sato N.
  • Journal Title: Carcinogenesis Volume: 33 Issue: 5 Pages: 996-1003
  • DOI: 10.1093/carcin/bgs118
  • Peer Reviewed
• [Journal Article] Efficiency of G2/M-related tumor-associated antigen-targeting cancer immunotherapy depends on antigen expression in the cancer stem-like population (2012)
  • Author(s): Takashi Mori, Satoshi Nishizawa, Yoshihiko Hirohashi, Toshihiko Torigoe, Yasuaki Tamura, Akari Takahashi, Vitaly Kochin, Reona Fujii, Kondo Toru, Mark I. Greene, Isao Hara, Noriyuki Sato
  • Journal Title: Experimental and Molecular Pathology Volume: 92 Issue: 1 Pages: 27-32
  • DOI: 10.1016/j.yexmp.2011.09.016
  • Peer Reviewed
• [Journal Article] New paradigm for intrinsic function of heat shock proteins as endogenous ligands in inflammation and innate immunity. (2012)
  • Author(s): Tamura Y, Torigoe T, Kutomi G, Hirata K, Sato N.
  • Journal Title: Curr Mol Med. Volume: 12 Pages: 1198-1206
  • Peer Reviewed
• [Journal Article] SOX2 is expressed in stem-like cells of human lung adenocarcinoma and augments the tumor-initiating potential (2011)
  • Author(s): Nakatsugawa, M., Takahashi, A., Hirohashi, Y., Torigoe, T., Inoda, S., Asanuma, H., Tamura, Y., Hasegawa, T., Takahashi, H., and Sato, N.
  • Journal Title: Lab Invest. Volume: 91 Issue: 12 Pages: 1796-1804
  • DOI: 10.1038/labinvest.2011.140
  • Peer Reviewed
• [Journal Article] Tumor-Produced Secreted Form of Binding of Immunoglobulin Protein Elicits Antigen-Specific Tumor Immunity. (2011)
  • Author(s): Tamura Y, Hirohashi Y, Kutomi G, Nakanishi K, Kamiguchi K, Torigoe T, Sato N.
  • Journal Title: J. Immunol Volume: 186 Issue: 7 Pages: 4325-4330
  • DOI: 10.4049/jimmunol.1004048
  • Peer Reviewed
• [Journal Article] Extracellular heat shock protein 90 plays a role in translocating chaperoned antigen from endosome to proteasome for generating antigenic peptide to be cross-presented by dendritic cells. (2011)
  • Author(s): Oura, J., Tamura, Y., Kamiguchi, K., Kutomi, G., Sahara, H., Torigoe, T., Himi, T., and Sato, N.
  • Journal Title: Int. Immunol Volume: 23 Issue: 4 Pages: 223-237
  • DOI: 10.1093/intimm/dxq475
  • Peer Reviewed
• [Journal Article] Immunogenic enhancement and clinical effect by type-I interferon of anti-apoptotic protein, survivin-derived peptide vaccine, in advanced colorectal cancer patients (2011)
  • Author(s): Kameshima, H., Tsuruma, T., Torigoe, T., Takahashi, A., Hirohashi, Y., Tamura, Y., Tsukahara, T., Ichimiya, S., Kanaseki, T., Iwayama, Y., Sato, N., Hirata, K.
  • Journal Title: Cancer Sci Volume: 102 Issue: 6 Pages: 1181-1187
  • DOI: 10.1111/j.1349-7006.2011.01918.x
  • NAID: 10029294487
  • Peer Reviewed
• [Journal Article] Comparison of speedy PCR-ssp method and serological typing of hla-a24 for Japanese cancer patients. (2011)
  • Author(s): Nakatsugawa M, Hirohashi Y, Torigoe T, Inoda S, Kiriyama K, Tamura Y, Sato E, Takahashi H, Sato N.
  • Journal Title: J Immunoassay Immunochem Volume: 32 Issue: 2 Pages: 93-102
  • DOI: 10.1080/15321819.2010.543219
  • Peer Reviewed
• [Journal Article] Cytotixic T lymphocytes efficiently recognize human colon cancer stem-like cells (2011)
  • Author(s): Inoda, S., Hirohashi, Y., Torigoe, T., Takahashi, A., Morita, R., Nakatsugawa, M., Nishizawa, S., Tamura, Y., Tsuruma, T., Terui, T., Ishitani, K., Hirata, K. and Sato, N.
  • Journal Title: Am. J. Pathol. Volume: 178 Issue: 4 Pages: 1805-1813
  • DOI: 10.1016/j.ajpath.2011.01.004
  • Peer Reviewed
• [Presentation] Tumor microenvironment and antitumor immunity) (2013)
  • Author(s): 田村保明, 鳥越俊彦, 佐藤昇志
  • Organizer: 第102回日本病理学会シンポジウム
  • Place of Presentation: 札幌
  • Year and Date: 2013-06-06
• [Presentation] Heat shock proteins act as endogenous enhancers building a bridge between innate immunity and adaptive immunity (2012)
  • Author(s): 田村保明
  • Organizer: 第71回日本癌学会学術総会シンポジウム
  • Place of Presentation: 札幌
  • Year and Date: 2012-09-20
• [Presentation] 熱ショック蛋白質HSPによる自己免疫疾患制御
  • Author(s): 田村保明
  • Organizer: 日本病理学会
  • Place of Presentation: 東京
• [Presentation] Hsp90による核酸系自然免疫リガンドの時空間的制御と免疫応答増強効果
  • Author(s): 田村保明
  • Organizer: 日本臨床ストレス応答学会
  • Place of Presentation: 名古屋
• [Presentation] 分泌型熱ショック蛋白質を用いた癌免疫療法
  • Author(s): 田村保明
  • Organizer: 日本免疫学会
  • Place of Presentation: 東京
• [Book] 分子標的薬熱ショック蛋白質(heat shock protein; HSP)系 (2012)
  • Author(s): 田村保明, 齋藤慶太, 佐藤昇志
  • Publisher: 日本臨床
• [Remarks]
  • URL: http://web.sapmed.ac.jp/patho1/