Improved immunogenicity of fusions between ethanol-treated cancer cells and dendritic cells exposed to dual TLR stimulation

• Project/Area Number: 23501289
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor immunology
• Research Institution: Jikei University School of Medicine
• Principal Investigator: KOIDO Shigeo 東京慈恵会医科大学, 医学部, 准教授 (70266617)
• Co-Investigator(Kenkyū-buntansha): HOMMA Sadamu 東京慈恵会医科大学, 医学部, 教授 (50192323)
• Project Period (FY): 2011-04-28 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 樹状細胞 / がん細胞 / がん免疫 / 細胞障害性Ｔ細胞 / がんワクチン / 融合細胞 / WT1 / 細胞障害性T細胞 / 膵癌 / トール様受容体 / 高免疫原性 / 樹状細胞ワクチン / 癌細胞 / TGF-beta / 細胞融合 / 癌 / 免疫療法 / 細胞傷害性Ｔ細胞 / 抑制性Ｔ細胞 / 免疫原性 / ワクチン / エタノール

Outline of Final Research Achievements

Fusions of ethanol-treated tumor cells and dual Toll-like receptors (TLRs)-stimulated dendritic cells (DCs) (E-tumor/FCs) inhibited the production of multiple immunesuppressive soluble factors including TGF-β1 and up-regulated the production of IL-12p70 and HSP90α. Importantly, E-tumor/FCs activated T cells capable of producing high levels of IFN-γ, resulting in augmented MUC1-specific cytotoxic T lymphocyte (CTL) induction. Collectively, our results illustrate the synergy between ethanol-treated whole tumor cells and dual TLRs-stimulated DCs in inducing augmented CTL responses in vitro by fusion cell preparations. The alternative system is simple and may provide a platform for adoptive immunotherapy.

Research Products

• [Journal Article] Induction of antigen-specific cytotoxic T lymphocytes by fusion cells generated from allogeneic plasmacytoid dendritic and tumor cells. (2014)
  • Author(s): Koido S, Homma S et al.
  • Journal Title: Int J Oncol Volume: 45 Issue: 1 Pages: 470-478
  • DOI: 10.3892/ijo.2014.2433
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Tumor regression by CD4 T-cells primed with dendritic/tumor fusion cell vaccines. (2014)
  • Author(s): Koido S, Enomoto Y et al. 2014
  • Journal Title: Anticancer Res Volume: 34 Pages: 3917-3924
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Immunological assessment of cryotherapy in breast cancer patients. (2014)
  • Author(s): Koido S, Kinoshita S et al.
  • Journal Title: Anticancer Res Volume: 34 Pages: 4869-4876
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Treatment with chemotherapy and dendritic cells pulsed with multiple Wilms' tumor 1 (WT1)-specific MHC class I/II-restricted epitopes for pancreatic cancer. (2014)
  • Author(s): Koido S, Homma S et al.
  • Journal Title: Clin Cancer Res Volume: 20 Issue: 16 Pages: 4228-39
  • DOI: 10.1158/1078-0432.ccr-14-0314
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Wilms tumor gene (WT1) peptide-based cancer vaccine combined with gemcitabine for patients with advanced pancreatic cancer. (2014)
  • Author(s): Nishida S, Koido S et al
  • Journal Title: J Immunother Volume: 37 Issue: 2 Pages: 105-114
  • DOI: 10.1097/cji.0000000000000020
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Combined TLR2/4-activated dendritic/tumor cell fusions induce augmented cytotoxic T lymphocytes (2013)
  • Author(s): Shigeo Koido
  • Journal Title: PLOS ONE Volume: 8 Issue: 3 Pages: e59280-e59280
  • DOI: 10.1371/journal.pone.0059280
  • Peer Reviewed
• [Journal Article] Augmentation of antitumor immunity by fusions of ethanol-treated tumor cells and dendritic cells stimulated via dual TLRs through TGF-β1 blockade and IL-12p70 production. (2013)
  • Author(s): Koido S, Homma S, Okamoto M et al.
  • Journal Title: PLoS ONE Volume: 8(5) Issue: 5 Pages: e63498-e63498
  • DOI: 10.1371/journal.pone.0063498
  • Peer Reviewed
• [Journal Article] Characterization of structure and direct antigen presentation by dendritic/tumor fused cells as cancer vaccines. (2013)
  • Author(s): Koido S, Gong J.
  • Journal Title: Anticancer Res Volume: 33 Pages: 347-54
  • Peer Reviewed
• [Journal Article] Suppressive effects on regulatory T cell induction by cyclophosphamide and gemcitabine in vitro. (2012)
  • Author(s): Kan S, Hazama S, Maeda K, Inoue Y, Homma S, Koido S, Okamoto M, Oka M.
  • Journal Title: Anticancer Res Volume: 32 Pages: 5363-9
  • Peer Reviewed
• [Journal Article] Clinical and immunologic evaluation of dendritic cell-based immunotherapy in combination with gemcitabine and/or S-1 in the patients with advanced pancreatic carcinoma (2012)
  • Author(s): Kimura Y, et al
  • Journal Title: Pancreas Volume: 41 Issue: 2 Pages: 195-205
  • DOI: 10.1097/mpa.0b013e31822398c6
  • Peer Reviewed
• [Journal Article] Gemcitabine enhances Wilms' tumor gene Immunotherapy synergizes with chemotherapy targeting pancreatic cancer (2012)
  • Author(s): Koido S., Homma S., Ito M., et al.
  • Journal Title: Immunotherpy Volume: 4 Issue: 1 Pages: 5-7
  • DOI: 10.2217/imt.11.150
  • Peer Reviewed
• [Journal Article] Gemcitabine enhances Wilms' tumor gene WT1 expression and sensitizes human pancreatic cancer cells with WT1-specific T-cell-mediated antitumor immune response (2011)
  • Author(s): Takahara A, et al
  • Journal Title: Cancer Immunol Immunother Volume: 60(9) Issue: 9 Pages: 1289-97
  • DOI: 10.1007/s00262-011-1033-3
  • Peer Reviewed
• [Journal Article] Current immunotherapeutic approaches in pancreatic cancer (2011)
  • Author(s): Koido S., Homma S., Ito M., et al.
  • Journal Title: Clin Dev Immunol Volume: 267539 Pages: 1-15
  • DOI: 10.1155/2011/267539
  • Peer Reviewed
• [Presentation] ウイルムス腫瘍遺伝子産物（WT1）由来のヘルパーとキラーペプチドをマルチプル・パルスした樹状細胞ワクチンと化学療法を併用した新規免疫化学療法 (2014)
  • Author(s): 小井戸薫雄 本間定 田尻久雄
  • Organizer: Japan Digestive Disease Week 2014
  • Place of Presentation: 神戸
  • Year and Date: 2014-10-23 – 2014-10-26
• [Presentation] WT1 peptide-based cancer vaccine in combination with gemcitabine for advanced pancreatic cancer (2014)
  • Author(s): 西田 純幸, 小井戸 薫雄 など
  • Organizer: 第18回日本がん免疫学会
  • Place of Presentation: 愛媛県松山市
  • Year and Date: 2014-07-30 – 2014-08-01
• [Presentation] Dendritic cells pulsed with WT1-specific MHC class I/II restricted epitopes for pancreatic cancer (2014)
  • Author(s): 小井戸薫雄、本間定 など
  • Organizer: 第18回日本がん免疫学会
  • Place of Presentation: 愛媛県松山市
  • Year and Date: 2014-07-30 – 2014-08-01
• [Presentation] ゲムシタビンによるHER2 発現増強効果を利用した膵癌に対する新たな分子標的療法 (2014)
  • Author(s): KAN Shin、小井戸薫雄 など
  • Organizer: 第18回日本がん免疫学会
  • Place of Presentation: 愛媛県松山市
  • Year and Date: 2014-07-30 – 2014-08-01
• [Presentation] Dendritic cells pulsed with Wilms’ tumor gene 1 (WT1)-specific and MHC class I and II-restricted epitopes with gemcitabine induce antitumor immune responses in patients with advanced pancreatic cancer. (2014)
  • Author(s): Shigeo Koido et al.
  • Organizer: American Association for Cancer Research (AACR)
  • Place of Presentation: San Diego
  • Year and Date: 2014-04-05 – 2014-04-09
• [Presentation] Wilms’ tumor gene 1 (WT1) peptide-based cancer vaccine combined with gemcitabine for patients with advanced pancreatic cancer (2014)
  • Author(s): Shigeo Koido et al.
  • Organizer: American Association for Cancer Research (AACR)
  • Place of Presentation: San Diego
  • Year and Date: 2014-04-05 – 2014-04-09
• [Presentation] Fusions of TLR2/4-activated dendritic cells and whole tumor cells induce augmented cytotoxic T lymphocytes. (2013)
  • Author(s): Shigeo Koido, Kan Shin, Hayashi Kazumi et al.
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] WT1およびMUC1がん抗原ペプチドを用いた進行膵癌に対する樹状細胞ワクチン療法 (2013)
  • Author(s): 辻谷俊一、岡本正人、木村幸乃、本間 定、小井戸薫雄、高橋秀徳、掛地吉弘、前原喜彦
  • Organizer: 第67回日本消化器外科学会定期学術総会
  • Place of Presentation: シーガイアコンベンションセンター
• [Presentation] WT1 immune response against pancreatic cancer cells is enhanced by treatment with gemcitabine which up-regulates WT1 expression of the cancer cells (2012)
  • Author(s): Sadamu Homma, Akitaka Takahara, Shigeo Koido
  • Organizer: The 6th International Conference on WT1 in Human Neoplasia
  • Place of Presentation: Kyoto
• [Book] Immunotherapy for Pancreatic Cancer. Pancreatic Cancer - Molecular Mechanism and Targets (2012)
  • Author(s): Koido S, Homma S, Takahara A, Namiki Y, Komita H, Uchiyama K, Ohkusa T, Tajiri H
  • Publisher: InTech
• [Book] Immunotherapy for Pancreatic Cancer (2012)
  • Author(s): Koido S, Homma S, Takahara A, Namiki Y, Komita H, Uchiyama K, Ohkusa T, Tajiri H
  • Total Pages: 26
  • Publisher: INTECH