The development of combined cancer therapy targeting hypoxic microenvironment

• Project/Area Number: 24590448
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Hokkaido University (2013-2014); Sapporo Medical University (2012)
• Principal Investigator: TAMURA Yasuaki 北海道大学, フード&メディカルイノーべーション推進本部, 特任教授 (80322329)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2012: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 低酸素 / 酸化酵素 / 分子標的治療 / がんワクチン / MHC クラスI分子 / ジスルフィド結合 / ERO1-α / PDI / 腫瘍免疫 / G-CSF / MHC クラスI / VEGFA / 細胞周囲環境 / 免疫抑制性細胞 / がん幹細胞 / 乳がん / 上皮間葉転換 / がん抗原ペプチド / 細胞障害性T細胞 / 膵臓癌 / 大腸癌 / 乳癌

Outline of Final Research Achievements

ERO1-α is an ER-resident oxidase. ERO1-α and PDI play a central role in disulfide bond formation of secreted and cell surface molecules. We have recently demonstrated that various types of tumor cells expressed high levels of ERO1-α. In this study, we show that ERO1-α associates with PDI, calnexin and immature MHC class I before being incorporated into transporter-associated with antigen processing-1 (TAP-1)-associated peptide-loading complex. Importantly, ERO1-α regulates the redox state as well as cell surface expression of MHC class I, leading to alteration of susceptibility by CD8+ T cell. Similarly, the ERO1-α expression within cancer cells was associated with the expression level of MHC class I in colon cancer tissues. Thus, the cancer-associated ERO1-α regulates the expression of MHC class I molecule via oxidative protein folding within hypoxic tumor microenvironment.

Research Products

• [Journal Article] Cancer-associated oxidoreductase ERO1-α drives the production of tumor-promoting myeloid-derived suppressor cells via oxidative protein folding. (2015)
  • Author(s): Tsutomu Tanaka, Toshimitsu Kajiwara, Toshihiko Torigoe, Yoshiharu Okamoto, Noriyuki Sato, Yasuaki Tamura
  • Journal Title: J Immunology Volume: 194 Issue: 4 Pages: 2004-2010
  • DOI: 10.4049/jimmunol.1402538
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Heat shock protein 90 targets a chaperoned peptide to the static early endosome for efficient cross-presentation by human dendritic cells (2015)
  • Author(s): Tsutomu Tanaka, Koichi Okuya, Goro Kutomi, Akari Takaya, Toshimitsu Kajiwara, Takayuki Kanaseki, Tomohide Tsukahara, Yoshihiko Hirohashi, Toshihiko Torigoe, Koichi Hirata, Yoshiharu Okamoto, Noriyuki Sato, Yasuaki Tamura
  • Journal Title: Cancer Science Volume: 106 Issue: 1 Pages: 18-24
  • DOI: 10.1111/cas.12570
  • NAID: 120005593448
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Cancer-associated oxidase ERO1-α regulates the expression of MHC class I molecule via oxidative folding. (2015)
  • Author(s): Kazuharu Kukita, Yasuaki Tamura, Tsutomu Tanaka, Toshimitsu Kajiwara, Goro Kutomi, Keita Saito, Koichi Okuya, Akari Takaya, Takayuki Kanaseki, Tomohide Tsukahara, Yoshihiko Hirohashi, Toshihiko Torigoe, Tomohisa Furuhata, Koichi Hirata, Noriyuki Sato
  • Journal Title: J Immunology Volume: 197 Issue: 10 Pages: 0-0
  • DOI: 10.4049/jimmunol.1303228
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Heat shock protein 90 associates with Toll-like receptors 7/9 and mediates self-nucleic acid recognition in SLE. (2015)
  • Author(s): Saito K, Kukita K, Kutomi G, Okuya K, Asanuma H, Tabeya T, Naishiro Y, Yamamoto M, Takahashi H, Torigoe T, Nakai A, Shinomura Y, Hirata K, Sato N, Tamura Y.
  • Journal Title: Eur. J Immunology Volume: 0 Issue: 7 Pages: 0-0
  • DOI: 10.1002/eji.201445293
  • Peer Reviewed / Acknowledgement Compliant
• [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] 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: Experimental Cell Research Volume: 319 Pages: 2617-2626
  • 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] 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
• [Presentation] 腫瘍に高発現する酸化酵素ERO1-αは、腫瘍増殖環境を整える (2015)
  • Author(s): 田中 努、田村 保明、梶原 敏充、鳥越 俊彦、岡本 芳晴、佐藤 昇志
  • Organizer: 第104回日本病理学会総会
  • Place of Presentation: 名古屋市
  • Year and Date: 2015-04-30 – 2015-05-02
• [Presentation] 腫瘍に高発現する酸化酵素ERO1-αは、がん幹細胞形質の維持に関与する (2014)
  • Author(s): 田村 保明, 田中 努、梶原 敏充、鳥越 俊彦、岡本 芳晴、佐藤 昇志
  • Organizer: 第9回臨床ストレス応答学会
  • Place of Presentation: 岡山市
  • Year and Date: 2014-11-01 – 2014-11-02
• [Presentation] 腫瘍に高発現する酸化酵素ERO1-αは、腫瘍増殖環境を整える (2014)
  • Author(s): 田中 努、田村 保明、梶原 敏充、鳥越 俊彦、岡本 芳晴、佐藤 昇志
  • Organizer: 第9回臨床ストレス応答学会
  • Place of Presentation: 岡山市
  • Year and Date: 2014-11-01 – 2014-11-02
• [Presentation] Enhanced expression of endoplasmic reticulum disulfide oxidase 1-α (ERO1-α) inhibits anti-tumor immune response. (2014)
  • Author(s): 田中 努、田村 保明、久木田 和晴、梶原 敏充、鳥越 俊彦、岡本 芳晴、佐藤 昇志
  • Organizer: 第72回日本癌学会
  • Place of Presentation: 横浜市
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] 腫瘍高発現性酸化酵素ERO1-αとがん幹細胞形質維持 (2014)
  • Author(s): 田中 努、田村 保明、久木田 和晴、梶原 敏充、鳥越 俊彦、岡本 芳晴、佐藤 昇志
  • Organizer: 第103回日本病理学会総会
  • Place of Presentation: 広島市
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] 腫瘍高発現性酸化酵素ERO1-αとがん幹細胞形質の維持 (2014)
  • Author(s): 田中 努、田村 保明、久木田 和晴、梶原 敏充、鳥越 俊彦、岡本 芳晴、佐藤 昇志
  • Organizer: 第103回日本病理学会
  • Place of Presentation: 広島国際会議場 (広島県）
• [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
  • Place of Presentation: ロイトン札幌 (北海道）
  • Invited
• [Presentation] 腫瘍に高発現する酸化酵素ERO1-αは、がん幹細胞形質の維持に関与する (2013)
  • Author(s): 田中 努、田村 保明、久木田 和晴、梶原 敏充、鳥越 俊彦、岡本 芳晴、佐藤 昇志
  • Organizer: 第102回日本病理学会
  • Place of Presentation: ロイトン札幌 (北海道）
• [Presentation] Enhanced expression of endoplasmic reticulum disulfide oxidase 1-α (ERO1-α) inhibits anti-tumor immune response. (2013)
  • Author(s): 田中 努、田村 保明、久木田 和晴、梶原 敏充、鳥越 俊彦、岡本 芳晴、佐藤 昇志
  • Organizer: 日本癌学会
  • Place of Presentation: パシフィコ横浜 (神奈川県)
• [Presentation] ERO1-αによるMHC class I分子発現制御と 癌免疫療法に対する効果予測因子としての可能性 (2012)
  • Author(s): 久木田和晴、田村保明, 斎藤慶太, 鳥越俊彦, 平田公一, 佐藤昇志
  • Organizer: 日本癌学会総会
  • Place of Presentation: 札幌市
• [Presentation] ERO1-αによるMHC class I分子発現制御と 癌免疫療法に対する効果予測因子としての可能性 (2012)
  • Author(s): 田村保明, 久木田和晴, 斎藤慶太, 鳥越俊彦, 平田公一, 佐藤昇志
  • Organizer: 日本臨床ストレス応答学会
  • Place of Presentation: 東京都
• [Presentation] ERO1-αによるMHC class I分子発現制御と 癌免疫療法に対する効果予測因子としての可能性 (2012)
  • Author(s): 田村保明, 久木田和晴, 斎藤慶太, 鳥越俊彦, 平田公一, 佐藤昇志
  • Organizer: 日本免疫学会総会
  • Place of Presentation: 神戸市