Elucidation of molecular mechanism of immune evasion in malignant lymphoma

• Project/Area Number: 15K06840
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: University of Tsukuba (2017); Keio University (2015-2016)
• Principal Investigator: Sugihara Eiji 筑波大学, 国際産学連携本部, 助教 (50464996)
• 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: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 非ホジキンリンパ腫 / 腫瘍免疫 / Fas / Livin / リンパ腫 / マウスモデル / 免疫回避 / アポトーシス

Outline of Final Research Achievements

In this study, to examine how malignant lymphoma cells can escape from the immune system, our established mouse lymphoma model was analyzed. We found that Fas expression is downregulated in lymphoma cells, and that restoration of Fas expression by CD40 signal activation in lymphoma cells induces apoptosis triggered by cytotoxic T cells expressing Fas ligand. Furthermore, certain human lymphoma cell lines that highly express a member of Survivin family Livin show resistance to Fas-mediated apoptosis. Given that high expression of Livin is associated with poor prognosis in Non-Hodgkin's lymphoma patients, targeting Livin is a new therapeutic strategy for malignant lymphoma to restore anti-tumor immune activity by Fas-mediated apoptosis.

Research Products

• [Int'l Joint Research] Emory University(米国)
• [Journal Article] Development of a functional thyroid model based on an organoid culture system. (2018)
  • Author(s): Saito Y, Onishi N, Takami H, Seishima R, Inoue H, Hirata Y, Kameyama K, Tsuchihashi K, Sugihara E, Uchino S, Ito K, Kawakubo H, Takeuchi H, Kitagawa Y, Saya H, Nagano O.
  • Journal Title: Biochem Biophys Res Commun Volume: 497 Issue: 2 Pages: 783-789
  • DOI: 10.1016/j.bbrc.2018.02.154
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clofarabine exerts antileukemic activity against cytarabine-resistant B-cell precursor acute lymphoblastic leukemia with low deoxycytidine kinase expression (2018)
  • Author(s): Huang M、Inukai T、Miyake K、Tanaka Y、Kagami K、Abe M、Goto H、Minegishi M、Iwamoto S、Sugihara E、Watanabe A、Somazu S、Shinohara T、Oshiro H、Akahane K、Goi K、Sugita K
  • Journal Title: Cancer Med Volume: 印刷中 Issue: 4 Pages: 1297-1316
  • DOI: 10.1002/cam4.1323
  • Peer Reviewed / Open Access
• [Journal Article] A periostin antisense oligonucleotide suppresses bleomycin-induced formation of a lung premetastatic niche for melanoma (2018)
  • Author(s): Semba T、Sugihara E、Kamoshita N、Ueno S、Fukuda K、Yoshino M、Takao K、Yoshikawa K、Izuhara K、Arima Y、Suzuki M、Saya H
  • Journal Title: Cancer Sci Volume: 印刷中 Issue: 5 Pages: 1447-1454
  • DOI: 10.1111/cas.13554
  • NAID: 120007127783
  • Peer Reviewed / Open Access
• [Journal Article] Simvastatin-Induced Apoptosis in Osteosarcoma Cells: A Key Role of RhoA-AMPK/p38 MAPK Signaling in Antitumor Activity. (2017)
  • Author(s): Kamel WA, Sugihara E, Nobusue H, Yamaguchi-Iwai S, Onishi N, Maki K, Fukuchi Y, Matsuo K, Muto A, Saya H, Shimizu T.
  • Journal Title: Molecular Cancer Therapeutics Volume: 16 Issue: 1 Pages: 182-192
  • DOI: 10.1158/1535-7163.mct-16-0499
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] FZR1 loss increases sensitivity to DNA damage and consequently promotes murine and human B cell acute leukemia. (2017)
  • Author(s): Ishizawa J, Sugihara E, Kuninaka S, Mogushi K, Kojima K, Benton CB, Zhao R, Chachad D, Hashimoto N, Jacamo RO, Qiu Y, Yoo SY, Okamoto S, Andreeff M, Kornblau SM, Saya H.
  • Journal Title: Blood Volume: 129 Issue: 14 Pages: 1958-1968
  • DOI: 10.1182/blood-2016-07-726216
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CD44 variant-dependent redox status regulation in liver fluke-associated cholangiocarcinoma: a target for CCA treatment. (2016)
  • Author(s): Thanee M, Loilome W, Techasen A, Sugihara E, Okazaki S, Abe S, Ueda S, Masuko T, Namwat N, Khuntikeo N, Titapun A, Pairojkul C, Saya H, Yongvanit P.
  • Journal Title: Cancer Sci. Volume: 107 Issue: 7 Pages: 991-1000
  • DOI: 10.1111/cas.12967
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MIF maintains the tumorigenic capacity of brain tumor-initiating cells by directly inhibiting p53. (2015)
  • Author(s): Fukaya R, Ohta S, Yaguchi T, Matsuzaki Y, Sugihara E, Okano H, Saya H, Kawakami Y, Kawase T, Yoshida K, Toda M.
  • Journal Title: Cancer Res Volume: なし Issue: 9 Pages: 1011-1011
  • DOI: 10.1158/0008-5472.can-15-1011
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Synergistic antiproliferative effect of imatinib and adriamycin in platelet-derived growth factor receptor-expressing osteosarcoma cells. (2015)
  • Author(s): Yamaguchi SI, Ueki A, Sugihara E, Onishi N, Yaguchi T, Kawakami Y, Horiuchi K, Morioka H, Matsumoto M, Nakamura M, Muto A, Toyama Y, Saya H, Shimizu T.
  • Journal Title: Cancer Sci. Volume: 106 Issue: 7 Pages: 875-882
  • DOI: 10.1111/cas.12686
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Periostin Is a Key Niche Component for Wound Metastasis of Melanoma. (2015)
  • Author(s): Fukuda K, Sugihara E, Ohta S, Izuhara K, Funakoshi T, Amagai M, Saya H.
  • Journal Title: PLoS One Volume: 10 Issue: 6 Pages: e0129704-e0129704
  • DOI: 10.1371/journal.pone.0129704
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hair follicle-derived IL-7 and IL-15 mediate skin-resident memory T cell homeostasis and lymphoma. (2015)
  • Author(s): Adachi T, Kobayashi T, Sugihara E, Yamada T, Ikuta K, Pittaluga S, Saya H, Amagai M, Nagao K.
  • Journal Title: Nature Med. Volume: 21 Issue: 11 Pages: 1272-1279
  • DOI: 10.1038/nm.3962
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Livin confers the resistance to lymphoma-suppressive barrier by Fas restoration (2017)
  • Author(s): Sugihara E, Hashimoto N, Osuka S, Ueno S, Shimizu T, Okamoto S, Saya H.
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Development of a new mouse model for mature B cell lymphoma and resistance to Fas restoration-triggered apoptosis. (2016)
  • Author(s): Sugihara E, Hashimoto N, Osuka S, Ueno S, Shimizu T, Okamoto S, Saya H.
  • Organizer: The 58st annual meeting of American Society of Hematology
  • Place of Presentation: サンディエゴ、アメリカ
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] Targeting Livin with Fas-signal restoration is a potential therapy for Non-Hodgkin Lymphomas (2016)
  • Author(s): Sugihara E, Hashimoto N, Osuka S, Ueno S, Shimizu T, Okamoto S, Saya H.
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-14
• [Presentation] New mouse lymphoma model reveals the requirement for Fas downregulation in initiation and maintenance of lymphoma cells (2015)
  • Author(s): Sugihara E, Hashimoto N, Ueno S, Shimizu T, Saya H.
  • Organizer: 第74回日本癌学会総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-10-08
• [Presentation] New mouse model for mature B cell lymphoma revealing requirement for Fas downregulation in lymphomagenesis. (2015)
  • Author(s): Sugihara E, Hashimoto N, Ueno S, Saya H.
  • Organizer: ヨーロッパ血液学会 EHA
  • Place of Presentation: ウィーン、オーストリア
  • Year and Date: 2015-06-11
  • Int'l Joint Research
• [Presentation] Novel mouse model for mature B cell lymphoma reveals the requirement for Fas downregulation in lymphomagenesis. (2015)
  • Author(s): Sugihara E, Hashimoto N, Ueno S, Saya H.
  • Organizer: 米国癌学会 AACR
  • Place of Presentation: フィラデルフィア、米国
  • Year and Date: 2015-04-18
  • Int'l Joint Research
• [Remarks] 慶應義塾大学 医学部 先端医科学研究所 遺伝子制御研究部門
  • URL: http://genereg.jp/index.html
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