Functional significance of integrin-αvβ3 in the regulation of metastatic potential of malignant melanoma and its therapeutic implication

• Project/Area Number: 21689031
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Dermatology
• Research Institution: Hokkaido University
• Principal Investigator: JINUSHI Masahisa 北海道大学, 遺伝子病制御研究所, 准教授 (40318085)
• Project Period (FY): 2009 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥12,090,000 (Direct Cost: ¥9,300,000、Indirect Cost: ¥2,790,000); Fiscal Year 2010: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2009: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: 腫瘍免疫 / 免疫療法 / 皮膚腫瘍学 / 腫瘍生物学 / 臨床腫瘍学 / 悪性黒色腫 / インテグリンαvβ3 / MFG-E8 / 抗癌剤耐性 / DNA損傷応答 / 抗腫瘍免疫 / 死細胞貪食 / 樹状細胞

Research Abstract

We evaluated the role of integrin-αvβ3 on the regulation of prognosis and therapeutic response of malignant melanoma. The melanoma cells that acquire the resistance to anticancer drugs displayed a significant upregulation of integrin-αvβ3. The integrin-αvβ3 on the chemoresistant melanoma manipulates dendritic cells to induce tolerogenic activities, thereby impairing antitumor immune responses. These findings verified novel molecular machineries whereby tumor resistance to anticancer therapeutics is associated with impairment of host antitumor immunity.

Research Products

• [Journal Article] ATM-mediated DNA damage signals mediate immune escape through integrin αvβ3-dependent mechanisms. (2012)
  • Author(s): Jinushi M
  • Journal Title: Cancer Res Volume: 72 Issue: 1 Pages: 56-65
  • DOI: 10.1158/0008-5472.can-11-2028
  • Peer Reviewed
• [Journal Article] ATM-mediated DNA damage signals mediate immune evasion through integrin-αvβ3-mediated mechanisms (2012)
  • Author(s): Jinushi M, Chiba S, Baghdadi M, et al
  • Journal Title: Cancer Research Volume: 72 Pages: 56-65
  • Peer Reviewed
• [Journal Article] The role of innate immune signals in the regulation of antitumor immunity (2012)
  • Author(s): Jinushi M
  • Journal Title: OncoImmunology Volume: 1(2) Pages: 1-6
• [Journal Article] Chronic activation of DNA damage signals causes tumor immune evasion in the chemoresistant niche (2012)
  • Author(s): Jinushi M
  • Journal Title: OncoImmunology Volume: 1(3) Pages: 1-3
• [Journal Article] Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells (2011)
  • Author(s): Jinushi M, Chiba S, Yoshiyama H, Masutomi K, Kinoshita I, Dosaka-Akita H, Yagita H, Takaoka A, Tahara H.
  • Journal Title: Proc Natl Acad Sci USA Volume: 108巻 Issue: 30 Pages: 12425-30
  • DOI: 10.1073/pnas.1106645108
  • NAID: 10030575946
  • Peer Reviewed
• [Journal Article] Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells (2011)
  • Author(s): Jinushi M, Chiba S, Yoshiyama H, et al
  • Journal Title: Proceedings of National Academy of Sciences of United States of America Volume: 108 Pages: 12425-12430
  • NAID: 10030575946
  • Peer Reviewed
• [Journal Article] Active Immunotherapy Induces Antibody Responses that Target Tumor Angiogenesis (2010)
  • Author(s): Schoenfeld J, Jinushi M, Nakazaki Y, Wiener D, Park J, Soiffer R, Neuberg D, Mihm M, Hodi FS & Dranoff G.
  • Journal Title: Cancer Res. Volume: 70 Issue: 24 Pages: 10150-10160
  • DOI: 10.1158/0008-5472.can-10-1852
• [Journal Article] Milk Fat Globule EGF-8 blockade triggers tumor destruction through coordinated cell-autonomous and immune-mediated mechanisms (2009)
  • Author(s): Jinushi M, Sato M, Kanamoto A, Itoh A, Nagai S, Koyasu S, Dranoff G, and Tahara H.
  • Journal Title: Journal of Experimental Medicine Volume: 100巻 Issue: 6 Pages: 1389-1396
  • DOI: 10.1084/jem.20082614
  • Peer Reviewed
• [Journal Article] Cancer immunotherapy : current status and future perspective (2009)
  • Author(s): Masahisa Jinushi, et al.
  • Journal Title: Cancer Science 100 Pages: 1389-1396
  • Peer Reviewed
• [Journal Article] Milk-fat globule EGF-8 triggers tumor destruction through coordinated cell-autonomous and immune-mediated mechanisms (2009)
  • Author(s): Masahisa Jinushi, et al.
  • Journal Title: Journal of Experimental Medicine 206 Pages: 1317-1326
  • Peer Reviewed
• [Presentation] Tumor-associated dendritic cells suppress nucleic acids-mediated innate immune recognition by TIM-3-dependent mechanisms (2011)
  • Author(s): Jinushi M
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ(千葉市)
  • Year and Date: 2011-11-27
• [Presentation] Dendritic cell-derived TIM-3 is a universal repressor of nucleic acid-mediated antitumor innate immune responses (2011)
  • Author(s): Jinushi M
  • Organizer: Cold Spring Harbor Laboratory Meetings "Harnessing Immunity to Prevent and Treat Disease"
  • Place of Presentation: Cold Spring Harbor Laboratory, NY, USA
  • Year and Date: 2011-11-18
• [Presentation] ATM-mediated DNA damage signals suppress antitumor immunity by integrin αvβ3-dependent mechanisms (2011)
  • Author(s): Jinushi M
  • Organizer: 第70回日本癌学会学術集会
  • Place of Presentation: 名古屋国際会議場(名古屋市)
  • Year and Date: 2011-10-04
• [Presentation] Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses in MFG-E8-dependent manner (2011)
  • Author(s): Jinushi M
  • Organizer: 第9回日本臨床腫瘍学会
  • Place of Presentation: パシフィコ横浜(横浜市)
  • Year and Date: 2011-07-21
• [Presentation] ATM-mediated DNA damage signals suppress antitumor immunity by integrin-αvβ3-dependent mechanisms (2011)
  • Author(s): Jinushi M, Chiba S, Takaoka A, Uede T, Hideo Y
  • Organizer: 第68回日本癌学会学術集会
  • Place of Presentation: 名古屋(International Symposium)
• [Presentation] Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses in MFG-E8-dependent manner (2011)
  • Author(s): Jinushi M.
  • Organizer: 第9回日本臨床腫瘍学会
  • Place of Presentation: 横浜(シンポジウム)
• [Presentation] In situ antitumor immunotherapy with pharmacological blockade of MFG-E8 and chemotherapy against tumors (2010)
  • Author(s): Jinushi M, Tahara H & Dranoff G.
  • Organizer: "Immunology" session, 100^<th> AACR Annual Meeting
  • Place of Presentation: Washington DC, USA(Symposium)
• [Presentation] The role of tumor-derived MFG-E8 in triggering chemoresistance and immune suppression in patients with various solid tumors (2009)
  • Author(s): Masahisa Jinushi, et al.
  • Organizer: 100^<th> Annual Meeting for AACR
  • Place of Presentation: Colorado Convention Center(Denver, CO, USA)
  • Year and Date: 2009-04-18
• [Presentation] In situ antitumor immunotherapy with pharmacological blockade of MFG-E8 and chemotherapy against solid and hematological tumors (2009)
  • Author(s): Jinushi M, Dranoff G, Tahara H.
  • Organizer: 第68回日本癌学会学術集会
  • Place of Presentation: 横浜(Symposium)
• [Presentation] The critical role of MFG-E8 in inflammation and cancer (2009)
  • Author(s): Jinushi M & Tahara H.
  • Organizer: International Conference of Macrophage
  • Place of Presentation: Kanazawa, Japan
• [Presentation] MFG-E8: Negative regulator and potential biomarker to predict the clinical activities of GVAX (2009)
  • Author(s): Jinushi M.
  • Organizer: US-Japan Workshop on immunological molecular marker in oncology
  • Place of Presentation: Hawaii, USA
• [Remarks]
  • URL: http://www.igm.hokudai.ac.jp/vec/
• [Remarks]
  • URL: http://www.igm.hokudai.ac.jp/vec/
• [Patent(Industrial Property Rights)] 抗がん剤 (2009)
  • Inventor(s): 地主将久、田原秀晃
  • Industrial Property Rights Holder: 東京大学
  • Filing Date: 2009-04-28
  • Overseas