The CD47-SIRPa signaling blockade accelerates macrophage phagocytic activity against cancer cells

• Project/Area Number: 23249064
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General surgery
• Research Institution: Hiroshima University
• Principal Investigator: OHDAN Hideki 広島大学, 医歯薬保健学研究院, 教授 (10363061)
• Co-Investigator(Kenkyū-buntansha): IDE Kentaro 広島大学, 大学病院, 病院助教 (50511565) ; KOBAYASHI Takaaki 名古屋大学, 医学系(医)研究科(研究院), 寄付講座教授 (70314010) ; TAHARA Hidetoshi 広島大学, 医歯薬保健学研究院, 教授 (00271065) ; SHIMAMOTO Akira 広島大学, 医歯薬保健学研究院, 准教授 (70432713) ; TANAKA Yuka 広島大学, 医歯薬保健学研究院, 助教 (90432666) ; 安井 弥 広島大学, 医歯薬保健学研究院, 教授 (40191118)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥48,230,000 (Direct Cost: ¥37,100,000、Indirect Cost: ¥11,130,000); Fiscal Year 2013: ¥13,780,000 (Direct Cost: ¥10,600,000、Indirect Cost: ¥3,180,000); Fiscal Year 2012: ¥14,170,000 (Direct Cost: ¥10,900,000、Indirect Cost: ¥3,270,000); Fiscal Year 2011: ¥20,280,000 (Direct Cost: ¥15,600,000、Indirect Cost: ¥4,680,000)
• Keywords: 腫瘍免疫 / 免疫回避 / 分子標的治療 / 糖鎖抗原

Research Abstract

We investigated whether inhibition of CD47-SIRPa signaling increases macrophage phagocytic activity against cancer cells by using in vitro and in vivo mouse syngeneic models. CD47 knock down Hepa1-6 cells were significantly more sensitive to macrophage phagocytosis than parental Hepa1-6 cells in both of in vitro and in vivo phagocytosis assays, indicating the pivotal role of CD47-SIRPa interaction in restricting tumor cell killing. Addition of anti-SIRPa mAns markedly enhanced the phagocytic activity of peritoneal cavity macrophage against Hepa1-6 and CMT93 compared with the isotype-matched Ab treatment in both of the in vitro and in vivo phagocytosis assays. Thus, our results suggest that CD47-SIRPa signaling interaction is a therapeutic target for inhibiting the growth of cancer cells.

Research Products

• [Journal Article] Prevention of recurrence after curative treatment for hepatocellular carcinoma. (2013)
  • Author(s): Kobayashi T, Ishiyama K, Ohdan H.
  • Journal Title: Surg Today Volume: 43 Issue: 12 Pages: 1347-1354
  • DOI: 10.1007/s00595-012-0473-5
  • Peer Reviewed
• [Journal Article] Expression of recipient CD47 on rat insulinoma cell xenografts prevents macrophage-mediated rejection through SIRPα inhibitory signaling in mice (2013)
  • Author(s): Teraoka Y, Ide K, Morimoto H, Tahara H, Ohdan H
  • Journal Title: PLoS One Volume: 8(3) Issue: 3 Pages: e58359-e58359
  • DOI: 10.1371/journal.pone.0058359
  • Peer Reviewed
• [Journal Article] Mechanistic analysis of the antitumor efficacy of TRAIL-positive human natural killer cells (2012)
  • Author(s): Kajitani K, Tanaka Y, Ohdan H, Arihiro K, Kataoka T
  • Journal Title: Nihon Rinsho Volume: 7 Pages: 208-13
• [Journal Article] Mechanistic analysis of the antitumor efficacy of human natural killer cells against breast cancer cells (2012)
  • Author(s): Kajitani K, Tanaka Y, Arihiro K, Kataoka T, Ohdan H
  • Journal Title: Breast Cancer Res Treat Volume: (Epub ahead of print)
  • Peer Reviewed
• [Journal Article] Human CD47 expression permits survival of porcine cells in immunodeficient mice that express SIRPα capable of binding to human CD47 (2011)
  • Author(s): Wang C、Wang H, Ide K, Wang Y, Van Rooijen N, Ohdan H, Yang YG
  • Journal Title: Cell Transplant Volume: (Epub ahead of print)
  • Peer Reviewed
• [Journal Article] Significance of platelet count in the outcomes of hepatectomized patients with hepatocellular carcinoma exceeding the Milan criteria (2011)
  • Author(s): Amano H, Tashiro H, Oshita A, Kobayashi T, Tanimoto Y, Kuroda S, Tazawa H, Itamoto T, Asahara T, Ohdan H
  • Journal Title: J Gastrointest Surg Volume: 15 Issue: 7 Pages: 1173-1181
  • DOI: 10.1007/s11605-011-1538-2
  • Peer Reviewed
• [Journal Article] Impact of adjuvant immunotherapy using liver allograft-derived lymphocytes on bacteremia in living donor liver trahsplantation (2011)
  • Author(s): Tashiro H, Ishiyama K, Ohira M, Igarashi Y, Tahara H, Ide K, Onoe T, Tanaka Y, Ohdan H
  • Journal Title: Transplantation Volume: 92 Issue: 5 Pages: 575-580
  • DOI: 10.1097/tp.0b013e318225db92
  • Peer Reviewed
• [Journal Article] External Validation of two nomograms for predicting patients survival after hepatic resection for metastatic colorectal cancer (2011)
  • Author(s): Takakura Y, Okajima M, Kanemitsu Y, Kuroda S, Egi H, Hinoi T, Tashiro H, Ohdan H
  • Journal Title: World J Surg Volume: 35 Issue: 10 Pages: 2275-2282
  • DOI: 10.1007/s00268-011-1194-4
  • Peer Reviewed
• [Journal Article] Tumor-related factors do not influence the prognosis of solitary hepatocellular carcinoma after partial hepatectomy (2011)
  • Author(s): Kobayashi T, Itamoto T, Tashiro H, Amano H, Oshita A, Tanimoto Y, Kuroda S, Tazawa H, Ohdan H
  • Journal Title: J Surg Oncol Volume: 18 Pages: 689-699
  • NAID: 10029688478
  • Peer Reviewed
• [Presentation] The CD47-signaling regulatory protein alpha (SIRPα ) signaling blockade enhances macrophage phagocytic activity against cancer cells (2014)
  • Author(s): Tomoyuki Abe, Yuka Tanaka, Piao Jinlian, Naoki Tanimine, Kentaro Ide, Hideki Ohdan
  • Organizer: Transplant Congress
  • Place of Presentation: San Francisco, USA
• [Presentation] CD47-SIRPαシグナル遮断によるマクロファージ抗腫瘍活性の増強 (2014)
  • Author(s): 安部智之, 田 中友加, 谷峰直樹, 朴 金連, 矢野琢也, 坂井寛, 佐伯吉弘, 清水誠一,森本博司, 平田 文宏, 橋本慎二, 大平真裕,田 原裕之, 井手健太郎, 石山宏平, 小林剛,田 代裕尊, 大段秀樹
  • Organizer: 第114回日本外科学会定期学術集会
  • Place of Presentation: 京都
• [Presentation] The therapeutic targeting the CD47-signaling regulatory protein alpha 020004000600080001 00001 20001 40001 6000 φ only isotype control anti-CD47mAb anti-SIRPa mAb combined mAbs 2hr図Cellnumbers 5 . ト ラ ンス ウ ェ ルを 用 いたマ ウ ス 腹腔内マ ク ロファ ージ migration assay図6 . 大腸癌自 然発生マウ ス モデル(Cpc/Apc マウ ス ) を用いた抗 SIRPα 抗体の腫瘍増勢に与える 経時的変化501 01 5202530359wks 1 6wks 20wks 24wks 28wks isotype control Ab anti-SIRPa Ab p=0.05 p<0.05総腫瘍径(SIRPα ) signaling inhibition enhances macrophage phagocytic activity against cancer cells (2014)
  • Author(s): Tomoyuki Abe, Yuka Tanaka, Piao Jinlian, Naoki Tanimine, Kentaro Ide, Hideki Ohdan
  • Organizer: 第22回マクロファージ分子細胞生物学国際シンポジウム
  • Place of Presentation: 神戸
• [Presentation] The CD47-SIRPα signaling blockade accelerates macrophage phagocytic activity against hepatocellular carcinoma even under immunosuppressive conditions (2013)
  • Author(s): Tomoyuki Abe, Yuka Tanaka, Piao Jinlian, Naoki Tanimine, Kentaro Ide, Hideki Ohdan
  • Organizer: 3rd ESOT Basic Science Meeting
  • Place of Presentation: Paris, France
• [Presentation] The CD47-SIRPα signaling inhibition enhances macrophage phagocytic activity against hepatocellular carcinoma (2013)
  • Author(s): Tomoyuki Abe, Yuka Tanaka, Paku Kinren, Naoki Tanimine, Kentaro Ide, Hideki Ohdan
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] CD47-SIRPαシグナルを介した癌細胞免疫回避機構の解明とその制御法の開発 (2013)
  • Author(s): 安部智之, 田 中友加, 谷峰直樹, 朴 金連, 井手健太郎, 佐伯吉弘, 清水誠一, 森本博司, 平田文宏, 橋本慎二, 山下正博, 堀田龍一, 寺岡義布史, 田澤宏文, 石山宏平, 田代裕尊, 大段秀樹
  • Organizer: 第31回日本肝移植研究会
  • Place of Presentation: 熊本
• [Presentation] Blocking CD47-SIRPα signaling promotes the phagocytic activity of macrophages against hepatocellular carcinoma (2013)
  • Author(s): Tomoyuki Abe, Yuka Tanaka, Piao Jinlian, Naoki Tanimine, Kentaro Ide, Hideki Ohdan
  • Organizer: 14th American Transplant Congress
  • Place of Presentation: Seattle, USA
• [Presentation] CD47-SIRPαシグナルを介した癌細胞の免疫回避機構におけるマクロファージの役割 (2013)
  • Author(s): 安部智之, 田 中友加, 谷峰直樹, 朴 金連, 佐伯吉弘, 清水誠一, 森本博司, 平田文宏, 橋本慎二, 山下正博, 堀田龍一, 寺岡義布史, 田澤宏文, 井手健太郎, 石山宏平, 田代裕尊, 大段秀樹
  • Organizer: 第113回日本外科学会定期学術集会
  • Place of Presentation: 福岡
• [Presentation] CD47-SIRPαシグナルを介した癌細胞免疫回避機構の解明とその制御法の開発 (2013)
  • Author(s): 安部智之, 田中友加, 谷峰直樹, 朴金連, 井手健太郎, 佐伯吉弘, 清水誠一, 森本博司, 平田文宏, 橋本慎二, 大平真裕, 石山宏平, 田代裕尊, 大段秀樹.
  • Organizer: 第31回日本肝移植研究会
  • Place of Presentation: 熊本市
• [Presentation] Blocking CD47-SIRPα signaling promotes the phagocytic activity of macrophages against hepatocellular carcinoma (2013)
  • Author(s): Abe T, Tanaka Y, Piao JL, Tanimine N, Ide K, Ohdan H.
  • Organizer: American Transplant Congress 2013
  • Place of Presentation: Seattle, USA
• [Presentation] CD47-SIRPαシグナルを介した癌細胞の免疫回避機構におけるマクロファージの役割 (2013)
  • Author(s): 安部智之, 田中友加, 谷峰直樹, 朴金連, 井手健太郎, 五十嵐友香, 佐伯吉弘, 清水誠一, 森本博司, 平田文宏, 橋本慎二, 山下正博, 堀田龍一, 寺岡義布史, 田澤宏文, 石山宏平, 田代裕尊, 大段秀樹.
  • Organizer: 第113回日本外科学会定期学術集会
  • Place of Presentation: 福岡市
• [Presentation] The CD47-SIRPα signaling inhibition enhances macrophage phagocytic activity against hepatocellular carcinoma (2013)
  • Author(s): Abe T, Tanaka Y, Piao JL, Tanimine N, Ide K, Ohdan H.
  • Organizer: 第７２回日本癌学会総会
  • Place of Presentation: 横浜市
• [Presentation] The CD47-SIRPα signaling blockade accelerates macrophage phagocytic activity against hepatocellular carcinoma even under immunosuppressive conditions (2013)
  • Author(s): Abe T, Tanaka Y, Piao J, Tanimine N, Ide K, Ohdan H.
  • Organizer: TTS Basic Science Meeting
  • Place of Presentation: Paris, France
• [Presentation] Blocking CD47-SIRPα signaling enhances the phagocytic activity of liver-resident macrophages against hepatocellular carcinoma (2012)
  • Author(s): Tomoyuki Abe, Yuka Tanaka, Piao Jinlian, Naoki Tanimine, Kentaro Ide, Hideki Ohdan
  • Organizer: 13th American Transplant Congress
  • Place of Presentation: Boston, USA
• [Presentation] Blocking CD47-SIRPα Signaling Enhances the Phagocytic Activity of Liver-Resident Macrophages Against Hepatocellular Carcinoma. (2012)
  • Author(s): Abe T, Tanaka Y, Tanimine N, Onoe T, Ide K, Ishiyama K, Ohdan H.
  • Organizer: American Transplantation Congress
  • Place of Presentation: Boston, USA
• [Presentation] Genetic Induction of Recipient CD47 on Xenografts Prevents Macrophage-Mediated Rejection through CD47-SIRPα Inhibitory Signaling: Evidence from an In Vivo Xenograft Model. (2012)
  • Author(s): Teraoka Y, Teraoka Y, Ide K, Morimoto H, Ohdan H.
  • Organizer: American Transplantation Congress
  • Place of Presentation: Boston, USA
• [Presentation] Necessity for Genetic Induction of Recipient CD47 to Prevent Macrophage-Mediated Xenograft Rejection through CD47-SIRPα Inhibitory Signaling. (2012)
  • Author(s): Teraoka Y, Teraoka Y, Ide K, Morimoto H, Ohdan H.
  • Organizer: 24th International congress of the transplantation society
  • Place of Presentation: Berlin, Germany
• [Presentation] Genetic induction of mouse CD47 on rat insulinoma cells prevents macrophage-mediated xenograft rejection through CD47-SIRPα inhibitory signaling in mice (2011)
  • Author(s): Teraoka Y, Ide K, Tahara H, Basnet N, Morimoto H, Ohdan H
  • Organizer: American Transplant Congress 2011
  • Place of Presentation: Philadelphia, America
• [Presentation] Differential susceptibility of B-cell subsets to proteasome inhibition : Bortezomib targets both IgM-producing B-1-like cells and IgG-producing plasma cells (2011)
  • Author(s): Tazawa H, Irei T, Igarashi Y, Tanaka Y, Ohdan H
  • Organizer: American Transplant Congress 2011
  • Place of Presentation: Philadelphia, America
• [Presentation] Pivotal role of invariant NKT cell-B cell interaction in antibody production against transplant-associated carbohydrate epitopes (2011)
  • Author(s): Tazawa H, Irei T, Igarashi Y, Tanaka Y, Ohdan H
  • Organizer: Basic Science Sympocium
  • Place of Presentation: Boston, America
• [Presentation] Adoptive immunotherapy for inducing anti-HCC and anti-HCV activity after liver transplantation (2011)
  • Author(s): Ohdan H
  • Organizer: 21st World congress of the international association of surgeons, gastroenterologists and oncologists
  • Place of Presentation: 東京(招待講演)
• [Presentation] Role of macrophage in transplantation (2011)
  • Author(s): Ohdan H
  • Organizer: The 2011 fall conference of the Korean association of immunologists
  • Place of Presentation: Korea, Seoul(招待講演)
• [Presentation] TRAIL陽性NK細胞を用いたNK療法の可能性 (2011)
  • Author(s): 梶谷桂子, 田中友加, 五十嵐有香, 片岡健, 大段秀樹
  • Organizer: 第19回日本乳癌学会学術総会
  • Place of Presentation: 仙台
• [Presentation] HCCを合併した肝移植患者に対する術後補助療法の確立-活性化NK細胞療法の臨床経過報告- (2011)
  • Author(s): 堀田龍一, 石山宏平, 大平真裕, 五十嵐友香, 田中友加, 井手健太郎, 尾上隆司, 田代裕尊, 大段秀樹
  • Organizer: 第47回日本移植学会総会
  • Place of Presentation: 仙台