Cancer vaccines targeting tumor blood vessels in GIST

• Project/Area Number: 25460936
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Jikei University School of Medicine
• Principal Investigator: KOMITA HIDEO 東京慈恵会医科大学, 医学部, 講師 (90534561)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: GIST / 免疫チェックポイント分子 / Tim-3 / Galectin-9 / NK細胞 / immunetherapy / 免疫チェックポイント機構 / WT1 / Hemoglobin-beta1 / pericyte / EphA2 / Tolerance / Sunitinib malate / epitope spreading

Outline of Final Research Achievements

We have previously reported that human gastrointestinal stromal tumor (GIST)has immunogenic features but the antitumor immunity to GIST seems to be suppressed in vivo. In the present study, immune cell types infiltrated into the 19 GIST tissues and immune checkpoint molecules were identified by immunehistochemistry. All the GIST tissues were from local gastric lesions and obtained by the surgical procedure. Nineteen and 8 GIST tissues showed CD8+ T cell and CD56+ natural killer (NK) cell infiltration, respectively, and their infiltrations were strongly correlated. T cell immunoglobulin and mucin protein 3(Tim-3) expression was seen in 6/8 (75%) of NK cells. Galectin-9 expression was observed in 13/19 (68.4%) of GIST tissues, and all the GIST tissues with Tim-3+NK cell infiltration showed positive galectin-9 expression. Tim-3/galectin-9 interaction between NK cells and GIST tumor cells might be involved in the suppression of antitumor immunity in GIST.

Research Products

• [Journal Article] Expression of immune checkpoint molecules of T cell immunoglobulin and mucin protein 3/galectin-9 for NK cell suppression on human gastrointestinal stromal tumors. (2015)
  • Author(s): Komita H, Koido S, Hayashi K, Kan S, Ito M, Kamata Y, Suzuki M, Homma S
  • Journal Title: Oncology Rep. Volume: 34 Issue: 4 Pages: 2099-105
  • DOI: 10.3892/or.2015.4149
  • Peer Reviewed
• [Journal Article] Up-regulation of HER2 by gemcitabine enhances the anti tumor effect of combined gemcitabine and trastumabemtasine treatment on pancreatic ductal adenocarcinoma cells. (2015)
  • Author(s): Kan S, Koido S, Okamoto M, Hayashi K, Ito M, Kamata Y, Komita H, Nagasaki E, Homma S.
  • Journal Title: BMC Cancer. Volume: 15 Issue: 1 Pages: 726-726
  • DOI: 10.1186/s12885-015-1772-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gemcitabine treatment enhances HER2 expression in low HER2-expressing breast cancer cells and enhances the anti tumor effects of traszumab emtasine. (2015)
  • Author(s): Kan S, Koido S, Okamoto M, Hayashi K, Ito M, Kamata Y, Komita H, Nagasaki E, Homma S.
  • Journal Title: Oncol Rep. Volume: 34 Issue: 1 Pages: 504-10
  • DOI: 10.3892/or.2015.3974
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Production of corticotropin-released factor and urocortin from human monocyte-derived dendritic cells is stimulated by commensal bacteria in intestine. (2014)
  • Author(s): Koido S, Ohkusa T, Kan S, Takakura K, Saito K, Komita H, Ito Z, Kobayashi H, Takami S, Uchiyama K, Arakawa H, Ito M, Okamoto M, Kajihara M, Homma S, Tajiri H.
  • Journal Title: World J Gastroenterol. Volume: 20 Issue: 39 Pages: 14420-9
  • DOI: 10.3748/wjg.v20.i39.14420
  • Peer Reviewed
• [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] Vaccination with vascular progenitor cells derived from induced pluripotent stem cells elicits antitumor immunity targeting vascular and tumor cells. (2014)
  • Author(s): 1.Koido S, Ito M, Sagawa Y, Okamoto M, Hayashi K, Nagasaki E, Kan S, Komita H, Kamata Y, Homma S.
  • Journal Title: Cancer Immunology Immunotherapy Volume: 63 Issue: 5 Pages: 459-468
  • DOI: 10.1007/s00262-014-1531-1
  • Peer Reviewed
• [Journal Article] Wilm's tumor gene(WT1) peptide-based cancer vaccine combined with gemcitabine for patients with advanced pancreatic cancer. (2014)
  • Author(s): Nishida S, Koido S, Takeda Y, Homma S, Komita H, Takahara A, Morita S, Ito T, Morimoto S, Hara K, Tsuboi A, Oka Y, Yanagisawa S, Toyama Y, Ikegami T, Kitagawa T, Eguchi H, Wada H, Nagano H, Nakata J, Nakae Y, Hosen N, Oji Y, Tanaka T, Kawase I, Kumanogoh A, Sakamoto J, Doki Y, MoriM, Ohkusa T, Tajiri H, Sugiyama H.
  • Journal Title: J Immunoher. Volume: 37 Pages: 105-14
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Strategies to improve the immunogenicity of anticancer vaccines based on dendritic cell/malignant cell fusions. (2013)
  • Author(s): Koido S, Homma S, Okamoto M, Namiki Y, Takakura K, Uchiyama K, Kajihara M, Arihiro S, Imazu H, Arakawa H, Kan S, Komita H,Kamata Y, Ito M, Ohkusa T, Gong J, Tajiri H.
  • Journal Title: Oncoimmunology Volume: 2(9)
  • Peer Reviewed
• [Journal Article] Fusions between dendritic cells and whole tumor cells as anticancer vaccines. (2013)
  • Author(s): Koido S, Homma S, Okamoto M, Namiki Y, Takakura K, Uchiyama K, Kajihara M, Arihiro S, Imazu H, Arakawa H, Kan S, Komita H, Ito M, Ohkusa T, Gong J, Tajiri H.
  • Journal Title: Oncoimmunology Volume: 2(5)
  • 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] Combined TLR2/4-activated dendritic/tumor cell fusions induce augmented cytotoxic T lymphocytes. (2013)
  • Author(s): Koido S, Homma S, Okamoto M, Namiki Y, Takakura K, Takahara A, Odahara S, Tsukinaga S, Yukawa T, Mitobe J, Matsudaira H, Nagatsuma K, Uchiyama K, Kajihara M, Arihiro S, Imazu H, Arakawa H, Kan S, Komita H, Ito M, Ohkusa T, Gong J, Tajiri H.
  • Journal Title: PloS One. Volume: 8(3)
  • Peer Reviewed
• [Presentation] セリンプロテアーゼ阻害剤はがん細胞のIFN-γ誘導性PD-L1の発現上昇を抑制する (2015)
  • Author(s): 佐川由紀子、林和美、小井戸薫雄、カンシン、込田英夫、鎌田裕子、伊藤正紀、本間定
  • Organizer: 第７４回日本癌学会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-10-09
• [Presentation] 進行膵癌患者血中の可溶性PDL-1 (2015)
  • Author(s): 本間定、小井戸薫雄、佐川由紀子、林和美、込田英夫、鎌田裕子、伊藤正紀
  • Organizer: 第７４回日本癌学会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-10-09
• [Presentation] GISTにおける免疫チェックポイント関連分子Tim-3/galectin-9の発現 (2015)
  • Author(s): 込田英夫、小井戸薫雄、林和美、伊藤正紀、鎌田裕子、田尻久雄、鈴木正章、本間定
  • Organizer: 第７４回日本癌学会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-10-08
• [Presentation] Tim-3/galectin-9interaction might be associated with the immunosuppression of Gastrointestinal stromal tumor(GIST) (2015)
  • Author(s): Hideo Komita, Shigeo Koido, Hisao Tajiri, Masafumi Suzuki, Sadamu Homma
  • Organizer: 2015 AACR annual meeting
  • Place of Presentation: Pennsylvania Convention Center
  • Year and Date: 2015-04-20
  • Int'l Joint Research
• [Presentation] 難治性消化管間葉系腫瘍(GIST)に対する癌免疫療法の検討 (2014)
  • Author(s): 込田 英夫、小井戸薫雄、カン シン、小林由紀子、林和美、鎌田裕子、伊藤正紀、鈴木正章、田尻久雄、本間定
  • Organizer: 第２７回日本バイオセラピー学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-12-04
• [Presentation] Gastrointestinal stromal tumors might be immunogenic to become a new target of cancer immunotherapy. (2014)
  • Author(s): Hideo Komita, Shigeo Koido, Shin Kan, Masaki Ito, Yuko Kamata, Yukiko Kobayashi, Kouji Nakata, Norio Mitsumori, Naoto Takahashi, Kazuto Tuboi, Masafumi Suzuki, Hisao Tajiri, Sadamu Homma.
  • Organizer: 第７３回日本癌学会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25
• [Presentation] 消化管間葉系腫瘍に対するWT1発現の検討
  • Author(s): 込田英夫、小井戸薫雄、鈴木正章、田尻久雄、本間定
  • Organizer: WT1研究会
  • Place of Presentation: 大阪大学
• [Presentation] 進行膵癌に対するWT1ペプチドワクチンとゲムシタビンによる集学的治療法の選択基準
  • Author(s): 小井戸薫雄、西田純幸、本間定、込田英夫、高原映崇、高倉一樹、内山幹、今津博雄、荒川廣志、大草敏史、田尻久雄
  • Organizer: JDDW 2013 Tokyo
  • Place of Presentation: 東京 品川
• [Presentation] 腹部超音波検査で肝血管腫所見を経過観察中肝細胞癌と診断、切除に至った一例
  • Author(s): 込田英夫、伊藤恭子、國安祐二、久保恭仁、小田彩、中崎薫、真島香代子、常喜眞理、銭谷幹夫、和田高士
  • Organizer: 人間ドック学会
  • Place of Presentation: 静岡県浜松
• [Presentation] 人間ドック受診者の非アルコール性脂肪肝における肝線維化指標FIB-4 indexの分布
  • Author(s): 和田高士、銭谷幹男、國安祐二、伊藤恭子、込田英夫、久保恭仁、真島香代子、前田俊彦、常喜眞理
  • Organizer: 人間ドック学会
  • Place of Presentation: 静岡県浜松