Basic research on development of dendritic cell therapy targeting glioma cancer stem cells

• Project/Area Number: 15K10346
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Kansai Medical University
• Principal Investigator: ASAI Akio 関西医科大学, 医学部, 教授 (50231858)
• Co-Investigator(Kenkyū-buntansha): 岩田 亮一 関西医科大学, 医学部, 助教 (60580446) ; 伊藤 量基 関西医科大学, 医学部, 准教授 (70434826)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: グリオーマ / 膠芽腫 / 癌幹細胞 / 樹状細胞 / 免疫抑制 / 免疫治療 / テモゾロミド / がん幹細胞

Outline of Final Research Achievements

Glioblastoma multiforme (GBM) is the most fatal malignant primary brain tumor. GBM contains functional subsets of cells called glioblastoma stem-like cells (GSCs), which are radioresistant and chemoresistant and eventually lead to tumor recurrence. We established GSCs lines and analyzed the expression of immune-associated molecules. GSCs lines were positive for MHC-Ⅰ, which indicated that GSCs can be recognized by T cells. Temozolomide (TMZ) is an oral alkylating agent with established anti-tumor activity in patients with GBM. We focused on the TMZ function and explored its influence on human dendritic cells (DCs) subsets. TMZ suppressed the secretion of IL-10 from DCs. Moreover, the addition of TMZ into peripheral blood mononuclear cells with DCs significantly enhanced the DC mediated ex vivo expansion and expression of cytotoxic molecules in CD8+ T cells. Our present findings suggest that TMZ is a potential anti-tumor reagent suitable for the combination use with DC-vaccine therapy.

Research Products

• [Journal Article] 転移性脳腫瘍とがん幹細胞の関連 (2018)
  • Author(s): 岩田亮一，丸山正人，大舟晃平，中野洋輔，大江総一，林美樹夫, 吉村晋一，埜中正博，淺井昭雄
  • Journal Title: Cytometry Research Volume: in press
  • Peer Reviewed / Open Access
• [Journal Article] Elevation of autoantibody level against PDCD11 in patients with transient ischemic attack (2017)
  • Author(s): Yoshida Y, Wang H, Hiwasa T, Machida T, Takiguchi M, Iwadate Y, et al.
  • Journal Title: Oncotarget Volume: 9 Issue: 3 Pages: 8836-8848
  • DOI: 10.1007/s11060-018-2831-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Enlarging pediatric ectopic Rathke's cleft cyst in the prepontine cistern: case report. (2017)
  • Author(s): Kamei T, Nonaka M, Uemura Y, Yamanouchi Y, Komori Y, Iwata R, Takeda J, Hashiba T, Yoshimura K, Asai A
  • Journal Title: J Neurosurg Pediatr Volume: 20(5) Issue: 5 Pages: 480-484
  • DOI: 10.3171/2017.6.peds1727
  • Peer Reviewed / Open Access
• [Journal Article] 5-ALA fluorescence-guided endoscopic surgery for mixed germ cell tumors. (2017)
  • Author(s): Takeda J, Nonaka M, Li Y, Komori Y, Kamei T, Iwata R, Hashiba T, Yoshimura K, Asai A.
  • Journal Title: J Neurooncol Volume: 134(1) Issue: 1 Pages: 119-124
  • DOI: 10.1007/s11060-017-2494-9
  • Peer Reviewed / Open Access
• [Journal Article] Establishment of a tumor sphere cell line from a metastatic brain neuroendocrine tumor. (2017)
  • Author(s): Iwata R, Maruyama M, Ito T, Nakano Y, Kanemura Y, Koike T, Oe S, Yoshimura K, Nonaka M, Nomura S, Sugimoto T, Yamada H, Asai A.
  • Journal Title: Med Mol Morphol Volume: 50(4) Issue: 4 Pages: 211-219
  • DOI: 10.1007/s00795-017-0160-0
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide methylation profiles in primary intracranial germ cell tumors indicate a primordial germ cell origin for germinomas (2017)
  • Author(s): Fukushima S, Yamashita S, Kobayashi H, et al.; Intracranial Germ Cell Tumor Genome Analysis Consortium (The iGCTConsortium).
  • Journal Title: Acta Neuropathologica Volume: 133 Issue: 3 Pages: 445-462
  • DOI: 10.1007/s00401-017-1673-2
  • Peer Reviewed / Open Access
• [Journal Article] Application of transpulmonary thermodilution monitoring (PiCCO) in patients with neurogenic pulmonary edema and acute obstructive hydrocephalus due to a central neurocytoma: A case report. (2017)
  • Author(s): R Iwata, K Yoshimura, Y Fujita, T Uesaka, H Oshige, A Asai
  • Journal Title: Interdisciplinary Neurosurgery: Advanced Techniques and Case Management Volume: 8 Pages: 57-59
  • DOI: 10.1016/j.inat.2017.01.014
  • Peer Reviewed / Open Access
• [Journal Article] Hyperperfusion syndrome after clipping of an unruptured aneurysm by transsylvian approach: A Case Repot. (2017)
  • Author(s): R Iwata, K Yoshimura, Y Fujita, T Uesaka, H Oshige, A Asai
  • Journal Title: Interdisciplinary Neurosurgery: Advanced Techniques and Case Management. Volume: 8 Pages: 11-13
  • DOI: 10.1016/j.inat.2017.01.010
  • Peer Reviewed / Open Access
• [Journal Article] Serine/Threonine kinase MLK4 determines Mesenchymal Identity in Glioma Stem Cells in an NFkB-dependent manner (2016)
  • Author(s): Kim SH, Ezhilarasan R, Chhipa R, Ladner K, Phillips E, Sparks A, Taylor D, Furuta T, Sabit H, Kurozumi K, Kuroiwa T, Akio A, Gallego-Perez1 D, Sulman EP, Cheng S, Lee J, Nakada M, Guttridge D, DasGupta B, Goidts V, Bhat KP, Walker J, Nakano I.
  • Journal Title: Cancer Cell Volume: 29 Issue: 2 Pages: 201-213
  • DOI: 10.1016/j.ccell.2016.01.005
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Recurrent neomorphic mutations of MTOR in central nervous system and testicular germ cell tumors may be targeted for therapy (2016)
  • Author(s): Ichimura K, Fukushima S, Nagane M, The Intracranial Berm Cell Tumor Genome Analysis Consortium, et al
  • Journal Title: Acta Neuropathol Volume: Published online: 08 March Issue: 6 Pages: 889-901
  • DOI: 10.1007/s00401-016-1557-x
  • Peer Reviewed
• [Journal Article] 治療後長期間生存している悪性視神経膠腫の1 例. (2016)
  • Author(s): 藤原望, 中内正志, 正健一郎, 山田晴彦, 最所千晶, 岩田亮一, 亀井孝昌, 淺井昭雄, 髙橋寛二
  • Journal Title: 臨床眼科 Volume: 70 Pages: 1473-1478
  • Peer Reviewed
• [Journal Article] Recurrent neomorphic mutations of MTOR in central nervous system and testicular germ cell tumors may be targeted for therapy. (2016)
  • Author(s): Ichimura K, Nonaka M, Asai A, , Matsutani M, Shibata T, Nishikawa R; Intracranial Germ Cell Tumor Genome Analysis Consortium.
  • Journal Title: Acta neuropathologica Volume: - Pages: 1-13
  • Open Access / Int'l Joint Research
• [Presentation] Functional expression of inwardly rectifying K+ channel in glioblastoma stem-like cells. (2018)
  • Author(s): Hayashi M, Iwata R, Andharia1 N, Ofune K, Yoshimura K, Nonaka M, Asai A, Matsuda H
  • Organizer: The Journal of Physiological Sciences 2018
• [Presentation] Development of new therapies for glioblastoma multiforme targeting nonselective cation channels. (2017)
  • Author(s): Iwata R, Ofune K, Hayashi M, Yoshimura K, Nonaka M, Matsuda H, Asai A
  • Organizer: Neuro-Oncology 2017
  • Int'l Joint Research
• [Presentation] 「グリオーマがん幹細胞に対する非選択性陽イオンチャネルを標的とした治療効果」 (2017)
  • Author(s): 岩田亮一、大舟晃平、林美樹夫、羽柴哲夫、吉村晋一、埜中正博、松田博子、淺井昭雄
  • Organizer: 第35回日本脳腫瘍学会学術集会
• [Presentation] 「TRP channelを標的とした悪性脳腫瘍の治療法の開発」 (2017)
  • Author(s): 大舟晃平、岩田亮一、林美樹夫、吉村晋一、埜中正博、松田博子、淺井昭雄
  • Organizer: 第15回がんとハイポキシア研究会
• [Presentation] 「非選択性陽イオンチャネルを標的とした悪性脳腫瘍の治療法の開発」 (2017)
  • Author(s): 大舟晃平、岩田亮一、林美樹夫、吉村晋一、埜中正博、松田博子、淺井昭雄
  • Organizer: 第49回日本臨床分子形態学会総会・学術集会
• [Presentation] グリオーマがん幹細胞で発現するICOSLGの機能 (2017)
  • Author(s): 岩田亮一、大舟晃平、伊藤量基、丸山正人、大江聡一、羽柴哲夫、吉村晋一、埜中正博、山田久夫、淺井昭雄
  • Organizer: 第15回がんとハイポキシア研究会
• [Presentation] 転移性脳腫瘍からのがん幹細胞株樹立 (2017)
  • Author(s): 岩田亮一, 丸山正人, 中野洋輔, 小池太郎, 大江聡一, 吉村晋一, 埜中正博, 杉本哲夫, 山田久夫, 淺井昭雄
  • Organizer: 第27回日本サイトメトリー学会学術集会
• [Presentation] 神経内分泌腫瘍の転移脳組織からの癌幹細胞 (2017)
  • Author(s): 岩田亮一, 丸山正人, 伊藤量基, 中野洋輔, 小池太郎, 大江聡一, 吉村晋一, 埜中正博, 野村昌作, 杉本哲夫, 山田久夫, 淺井昭雄
  • Organizer: 第49回日本臨床分子形態学会総会・学術集会
• [Presentation] ヒト神経膠芽腫由来U87MG細胞から樹立した高い腫瘍形成能を持つスフェロイドはPC3-Secreted Microprotein を高発現する (2017)
  • Author(s): 丸山正人, 中野洋輔, 岩田亮一, 加瀬政彦, 杉本哲夫
  • Organizer: Conbio2017（生命科学系学会合同年次大会：第40回日本分子生物学会年会
• [Presentation] 内視鏡下5アミノレブリン酸（5-ALA）蛍光診断（PDD）～連続45症例の検討～. (2016)
  • Author(s): 武田純一, 埜中正博, 亀井孝昌, 岩田亮一, 羽柴哲夫, 吉村晋一, 淺井昭雄.
  • Organizer: 第34回日本脳腫瘍学会学術集会.
  • Place of Presentation: 甲府富士屋ホテル、山梨
  • Year and Date: 2016-12-04
• [Presentation] Effect of Temozolomide on Brain Metastasis of neuroendocrine carcinoma. (2016)
  • Author(s): Ryoichi Iwata, Masato Maruyama, Tomoki Ito, Yoko Fujita, Yoshiyuki Matsuo, Yosuke Nakano, Kunikazu Yoshimura, Masahiro Nonaka, Kiichi Hirota, Shosaku Nomura, Tetsuo Sugimoto, Akio Asai.
  • Organizer: The 13th Asian Society for Neuro-oncology (ASNO) Meeting.
  • Place of Presentation: Sheraton on the Park, Sydney, Australia
  • Year and Date: 2016-09-11
  • Int'l Joint Research
• [Presentation] Therapeutical Doses of Temozolomide Inhibit IL-10 Production by Dendritic Cells and Enhance the CTL Response. (2016)
  • Author(s): Akio Asai, Ryoichi Iwata, Tomoki Ito, Muneo Inaba, Noriko Katashiba, Kayoko Kibata, Akihiro Tanaka, Shosaku Nomura.
  • Organizer: The 21st International Conference on Brain Tumor Research and Therapy.
  • Place of Presentation: Bankoku Shinryokan, Okinawa
  • Year and Date: 2016-04-10
• [Presentation] グリオーマ癌幹細胞で発現するICOSリガンドを介した免疫制御機構の新展開 (2015)
  • Author(s): 岩田亮一, 伊藤量基, 稲葉宗夫, 小池太郎, 二宮英樹, 李一, 染野裕美子, 亀井孝昌, 武田純一, 大石哲也, 大重英行, 吉村晋一, 埜中正博, 山田久夫, 野村昌作, 中野伊知郎, 淺井昭雄
  • Organizer: 第33回日本脳腫瘍学会学術集会
  • Place of Presentation: 京都府京都市左京区宝ヶ池グランドプリンスホテル京都
  • Year and Date: 2015-12-06
• [Presentation] Mesenchymal type Glioma Stem Cell express ICOS Ligand and upregulate Tr1 cells (2015)
  • Author(s): Ryoichi Iwata, Tomoki Ito, Muneo Inaba, Taro Koike, Hideyuki Oshige, Kunikazu Yoshimura, Masahiro Nonaka, Hisao Yamada, Shosaku Nomura, Umberto Dianzani, Ichiro Nakano, Akio Asai
  • Organizer: the 20th Annual Scientific Meeting and Education Day of the Society for Neuro-Onclology
  • Place of Presentation: San Antonio,Texas, USA San Antonio Marriott Rivercenter
  • Year and Date: 2015-11-19
  • Int'l Joint Research
• [Presentation] Mesenchymal type Glioma Stem Cell express ICOS Ligand and upregulate ICOS+IL-10+Tcells (2015)
  • Author(s): 岩田亮一, 伊藤量基, 稲葉宗夫, 小池太郎, 大重英行, 吉村晋一, 埜中正博, 山田久夫, 野村昌作, 中野伊知郎, 淺井昭雄
  • Organizer: 第56回日本組織細胞化学会総会・学術集会
  • Place of Presentation: 大阪府枚方市新町関西医科大学枚方新キャンパス
  • Year and Date: 2015-10-03
• [Presentation] Therapeutical dose of Temozolomide inhibit IL-10 production by dendritic cells and enhance the CTL response (2015)
  • Author(s): Ryoichi Iwata, Tomoki Ito, Muneo Inaba, Noriko Katashiba, Kayoko Kibata, Akihiro Tanaka, Phan Thi Xuan Vien, Hideyuki Oshige, Kunikazu Yoshimura, Takehiro Suyama, Masahiro Nonaka, Shosaku Nomura, Akio Asai
  • Organizer: ASNO 2015 12th Meeting of the Asian Society for Neuro-Onclology
  • Place of Presentation: Pasay City Manila, Philippines Sofitel Philippine Plaza Hotel
  • Year and Date: 2015-09-17
  • Int'l Joint Research
• [Presentation] Mesenchymal typeのグリーマ癌幹細胞で発現するICOSリガンドは、IL-10産生T細胞を誘導する (2015)
  • Author(s): 岩田亮一, 伊藤量基, 稲葉宗夫, 小池太郎, 大重英行, 吉村晋一, 埜中正博, 山田久夫, 野村昌作, 中野伊知郎, 淺井昭雄
  • Organizer: 第25回日本サイトメトリー学会学術集会
  • Place of Presentation: 東京都千代田区神田駿河台ソラシティカンファレンスセンター
  • Year and Date: 2015-07-11
• [Presentation] 悪性神経膠腫におけるICOSリガンドを介した腫瘍免疫抑制機序について (2015)
  • Author(s): 岩田亮一, 伊藤量基, 小池太郎, 大重英行, 吉村晋一, 埜中正博, 山田久夫, 野村昌作, 中野伊知郎, 淺井昭雄
  • Organizer: 第33回日本脳腫瘍病理学会
  • Place of Presentation: 香川県高松市浜ノ町JRホテルクレメント高松
  • Year and Date: 2015-05-29
• [Book] 【脳腫瘍学-基礎研究と臨床研究の進歩-】 転移性脳腫瘍 転移性脳腫瘍の治療 (2016)
  • Author(s): 岩田亮一、淺井昭雄
  • Total Pages: 5
  • Publisher: 日本臨牀
• [Book] メディカ出版 (2015)
  • Author(s): 岩田亮一, 淺井昭雄
  • Total Pages: 400
  • Publisher: 中枢神経系感染症、脳神経外科救急ハンドブック 日本脳神経外科救急学会編 改訂第2版