Molecular mechanism of cancer immunosurveillance and its application to cancer therapy

2009 Fiscal Year Final Research Report

• Project/Area Number: 17016071
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Juntendo University
• Principal Investigator: YAGITA Hideo Juntendo University, 医学部, 先任准教授 (30182306)
• Project Period (FY): 2005 – 2009
• Keywords: がん / 免疫 / 抗体療法 / キラーT細胞 / ナチュラルキラー細胞

Research Abstract

By characterizing the molecular mechanism of tumor cell recognition and lysis by cytotoxic T cells and natural killer cells, we have developed the anti-DR5 therapy which mimics it. We have also developed novel strategies to augment anti-tumor immunity by using antibodies activating the immuno-stimulatory pathways (such as CD40, CD27, and 4-1BB) and those blocking the immuno-suppressive pathways (such as CTLA-4, PD-1, and B7-H3).

Research Products

• [Journal Article] Optimized combination therapy using bortezomib, TRAIL and TLR agonists in established breast tumors. (2010)
  • Author(s): Lee S, Yagita H, Sayers TJ, Celis E
  • Journal Title: Cancer Immunol Immunother (in press)
  • Peer Reviewed
• [Journal Article] Anti-tumor effects of depleting and non-depleting anti-CD27 monoclonal antibodies in immune-competent mice. (2010)
  • Author(s): Sakanishi T, Yagita H
  • Journal Title: Biochem Biophys Res Commun 393 Pages: 829-835
  • Peer Reviewed
• [Journal Article] PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. (2010)
  • Author(s): Curran MA, Montalvo W, Yagita H, Allison JP
  • Journal Title: Proc Natl Acad Sci USA 107 Pages: 4275-4280
  • Peer Reviewed
• [Journal Article] Tumor-reactive CD4+ T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts. (2010)
  • Author(s): Quezada SA, Simpson TR, Peggs KS, Merghoub T, Vider J, Fan X, Blasberg R, Yagita H, Muranski P, Antony PA, Restifo NP, Allison JP
  • Journal Title: J Exp Med 207 Pages: 637-650
  • Peer Reviewed
• [Journal Article] DNAM-1/CD155 interactions promote cytokine NK cell-mediated suppression of poorly immunogenic melanoma metastasis. (2010)
  • Author(s): Chan CJ, Andrew DM, McLaughlin NM, Yagita H, Gilfillan S, Colonna M, Smyth MJ
  • Journal Title: J Immunol 184 Pages: 902-911
  • Peer Reviewed
• [Journal Article] Targeting antigen to diverse APCs inactivates memory CD8+ T cells without eliciting tissue-destructive effector function. (2010)
  • Author(s): Kenna TJ, Waldie T, McNally A, Thomson M, Yagita H, Thomas R, Steptoe RJ
  • Journal Title: J Immunol 184 Pages: 598-606
  • Peer Reviewed
• [Journal Article] Clinical importance of B7-H3 expression in human pancreatic cancer. (2009)
  • Author(s): Yamato I, Sho M, Nomi T, Akahori T, Shimada K, Hotta K, Kanehiro H, Konishi N, Yagita H, Nakajima Y
  • Journal Title: Br J Cancer 101 Pages: 1709-1716
  • Peer Reviewed
• [Journal Article] Blockade of B7-H1 or B7-DC induces an anti-tumor effect in a mouse pancreatic cancer model. (2009)
  • Author(s): Okudaira K, Hokari R, Tsuzuki Y, Okada Y, Komoto S, Watanabe C, Kurihara C, Kawaguchi A, Nagao S, Azuma M, Yagita H, Miura S
  • Journal Title: Int J Oncol 35 Pages: 741-749
  • Peer Reviewed
• [Journal Article] Antigen presented by tumors in vivo determines the nature of CD8+ T cell cytotoxicity. (2009)
  • Author(s): Shanker A, Brooks AD, Jacobsen KM, Wine JW, Wiltrout RH, Yagita H, Sayers TJ
  • Journal Title: Cancer Res 69 Pages: 6615-6623
  • Peer Reviewed
• [Journal Article] Recall responses by helpless memory CD8+ T cells are restricted by the up-regulation of PD-1. (2009)
  • Author(s): Fuse S, Tsai C, Molloy MJ, Allie SR, Zhang W, Yagita H, Usherwood EJ
  • Journal Title: J Immunol 182 Pages: 4244-4254
  • Peer Reviewed
• [Journal Article] PD-1/PD-L blockade prevents anergy induction and enhances the anti-tumor activities of glycolipid-activated invariant NKT cells. (2009)
  • Author(s): Parekh VV, Lalani S, Kim S, Halder R, Azuma M, Yagita H, Kumar V, Wu L, Kaer LV
  • Journal Title: J Immunol 182 Pages: 2816-2826
  • Peer Reviewed
• [Journal Article] Tim-3 mediates phagocytosis of apoptotic cells and the cross-presentation. (2009)
  • Author(s): Nakayama M, Akiba H, Takeda K, Kojima Y, Hashiguchi M, Azuma M, Yagita H, Okumura K
  • Journal Title: Blood 113 Pages: 3821-3830
  • Peer Reviewed
• [Journal Article] NKG2A inhibits invariant NKT cell activation in hepatic injury. (2009)
  • Author(s): Kawamura T, Takeda K, Kaneda H, Matsumoto H, Hayakawa Y, Raulet DH, Ikarashi Y, Kronenberg M, Yagita H, Kinoshita K, Abo T, Okumura K, Smyth MJ
  • Journal Title: J Immunol 182 Pages: 250-258
  • Peer Reviewed
• [Journal Article] Differential effector mechanisms induced by vaccination with MUC1 DNA in the rejection of colon carcinoma growth at orthotopic sites and metastases. (2008)
  • Author(s): Sugiura D, Aida S, Denda-Nagai K, Takeda K, Kamata-Sakurai M, Yagita H, Irimura T
  • Journal Title: Cancer Sci 99 Pages: 2477-2484
  • Peer Reviewed
• [Journal Article] Programmed death-1/programmed death ligand 1 interaction regulates the induction and maintenance of invariant NKT cell anergy. (2008)
  • Author(s): Chang WS, Kim JY, Kim YJ, Kim YS, Lee JM, Azuma M, Yagita H, Kang CY
  • Journal Title: J Immunol 181 Pages: 6707-6710
  • Peer Reviewed
• [Journal Article] Antibodies targeted to TRAIL receptor-2 and ErbB-2 synergize in vivo and induce an antitumor immune response. (2008)
  • Author(s): Stagg J, Sharkey J, Pommey S, Young R, Takeda K, Yagita H, Johnstone RW, Smyth MJ
  • Journal Title: Proc Natl Acad Sci USA 105 Pages: 16254-16259
  • Peer Reviewed
• [Journal Article] CD4+CD25+ Tregs control the TRAIL-dependent cytotoxicity of tumor-infiltrating DCs in rodent models of colon cancer. (2008)
  • Author(s): Roux S, Apetoh L, Chalmin F, Ladoire S, Mignot G, Puig PE, Lauvau G, Zitvogel L, Martin F, Chauffert B, Yagita H, Solary E, Ghiringhelli F
  • Journal Title: J Clin Invest 118 Pages: 3751-3761
  • Peer Reviewed
• [Journal Article] Combination therapy of established cancer using a histone deacetylase inhibitor and a TRAIL receptor agonisit. (2008)
  • Author(s): Frew AJ, Lindemann RK, Martin BP, Clarke CJP, Sharkey J, Anthony DA, Banks KM, Haynes NM, Gangatirkar P, Stanley K, Bolden JE, Takeda K, Yagita H, Secrist JP, Smyth MJ, Johnstone RW
  • Journal Title: Proc Natl Acad Sci USA 105 Pages: 11317-11322
  • Peer Reviewed
• [Journal Article] Death receptor 5-mediated apoptosis contributes to cholestatic liver disease. (2008)
  • Author(s): Takeda K, Kojima Y, Ikejima K, Harada K, Yamashina S, Okumura K, Aoyama T, Frese F, Ikeda H, Haynes NM, Cretney E, Yagita H, Sueyoshi N, Sato N, Nakanuma Y, Smyth MJ, Okumura K
  • Journal Title: Proc Natl Acad Sci USA 105 Pages: 10895-10900
  • Peer Reviewed
• [Journal Article] Notch2 integrates signaling by the transcriptional factors RBP-J and CREB1 to promote T cell cytotoxicity. (2008)
  • Author(s): Maekawa Y, Minato Y, Ishifune C, Kurihara T, Kitamura A, Kojima H, Yagita H, Sakata-Yanagimoto M, Saito T, Taniuchi I, Chiba S, Sone S, Yasutomo K
  • Journal Title: Nature Immunol 9 Pages: 1140-1147
  • Peer Reviewed
• [Journal Article] Combination of treatment with death receptor 5-specific antibody with therapeutic HPV DNA vaccination generates enhanced therapeutic anti-tumor effects. (2008)
  • Author(s): Tseng CW, Trimble C, Monie C, Alvarez RD, Huh WK, Buchsbaum DJ, Straughn JM, Wang MC, Yagita H, Hung CF, Wu TC
  • Journal Title: Vaccine 26 Pages: 4314-4319
  • Peer Reviewed
• [Journal Article] Dendritic cell-mediated NK cell activation is controlled by Jagged2-Notch interaction. (2008)
  • Author(s): Kijima M, Yamaguchi T, Isifune C, Maekawa Y, Koyanagi A, Yagita H, Chiba S, Kishihara K, Shimada M, Yasutomo K
  • Journal Title: Proc Natl Acad Sci USA 105 Pages: 7010-7015
  • Peer Reviewed
• [Journal Article] Treating metastatic solid tumors with bortezomib and a tumor necrosis factor-related apoptosis-inducing ligand receptor agonist antibody. (2008)
  • Author(s): Shanker A, Brooks AD, Tristan CA, Wine JW, Elliot PJ, Yagita H, Takeda K, Smyth MJ, Murphy WJ, Sayers TJ
  • Journal Title: J. Natl. Cancer Inst 100 Pages: 649-662
  • Peer Reviewed
• [Journal Article] Interleukin 21 enhances antibody-mediated tumor rejection. (2008)
  • Author(s): Smyth MJ, Teng MWL, Sharkey J, Westwood JA, Haynes NM, Yagita H, Takeda K, Sivakumar PV, Kershaw MH
  • Journal Title: Cancer Res 68 Pages: 3019-3025
  • Peer Reviewed
• [Journal Article] Combined natural killer T-cell-based immunotherapy eradicates established tumors in mice. (2007)
  • Author(s): Teng MWL, Westwood JA, Darcy PK, Sharkey J, Tsuji M, Franck RW, Porcelli SA, Besra GS, Takeda K, Yagita H, Kershaw MH, Smyth MJ
  • Journal Title: Cancer Res 67 Pages: 7495-7504
  • Peer Reviewed
• [Journal Article] Differential engagement of Tim-1 during activation can positively or negatively costimulate T cell expansion and effector function. (2007)
  • Author(s): Xiao S, Najafian N, Reddy J, Albin M, Zhu C, Jensen E, Imitola J, Korn T, Anderson AC, Zhang Z, Gutierrez C, Moll T, Sobel RA, Umetsu DT, Yagita H, Akiba H, Strom T, Sayegh MH, DeKruyff RH, Khoury SJ, Kuchroo VK
  • Journal Title: J Exp Med 204 Pages: 1691-1702
  • Peer Reviewed
• [Journal Article] Tageting death-inducing receptors in cancer therapy. (2007)
  • Author(s): Takeda K, Stagg J, Yagita H, Okumura K, Smyth MJ
  • Journal Title: Oncogene 26 Pages: 3745-3757
  • Peer Reviewed
• [Journal Article] Perforin activity and immune homeaostasis: the common A91V polymorphism in perforin results in both pre- and post-synaptic defects in function. (2007)
  • Author(s): Voskoboinik I, Sutton VR, Ciccone A, House C, Chia J, Darcy PK, Yagita H, Trapani JA
  • Journal Title: Blood 110 Pages: 1184-1190
  • Peer Reviewed
• [Journal Article] A subset of dendritic cells induces CD4+ T cells to produce IFN-□by an IL-12-independent but CD70-dependent mechanism in vivo. (2007)
  • Author(s): Soares H, Waechter H, Glaichenhaus N, Mougneau E, Yagita H, Mizenina O, Dudziak D, Nussenzweig MC, Steinman RM
  • Journal Title: J Exp Med 204 Pages: 1095-1106
  • Peer Reviewed
• [Journal Article] Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. (2007)
  • Author(s): Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, Nakamura S, Enomoto K, Yagita H, Azuma M, Nakajima Y
  • Journal Title: Clin Cancer Res 13 Pages: 2151-2157
  • Peer Reviewed
• [Journal Article] Priming of CD8+ T cell responses by pathogens typically depends on CD70-mediated interactions with dendritic cells. (2007)
  • Author(s): Schildknecht A, Miescher I, Yagita H, van den Broek M
  • Journal Title: Eur J Immunol 37 Pages: 716-728
  • Peer Reviewed
• [Journal Article] Combined TLR/CD40 stimulation mediates potent immunity by regulating dendritic cell expression of CD70 in vivo. (2007)
  • Author(s): Sanchez PJ, McWilliams JA, Haluszczak C, Yagita H, Kedl RM
  • Journal Title: J Immunol 178 Pages: 1564-1572
  • Peer Reviewed
• [Journal Article] Programed death (PD) ligand-1/PD-1 interaction is required for CD8+ T cell tolerance to tissue antigens. (2006)
  • Author(s): Martin-Orozco N, Wang Y, Yagita H, Dong C
  • Journal Title: J Immunol 177 Pages: 8291-8295
  • Peer Reviewed
• [Journal Article] B7-H1-induced apoptosis as a mechanism of immune privilege of corneal allografts. (2006)
  • Author(s): Hori J, Wang M, Miyashita M, Tanemoto K, Takahashi H, Takemori T, Okumura K, Yagita H, Azuma M
  • Journal Title: J Immunol 177 Pages: 5928-5935
  • Peer Reviewed
• [Journal Article] Eradication of established tumors in mice by a combination antibody-based therapy. (2006)
  • Author(s): Uno T, Takeda K, Kojima Y, Yoshizawa H, Akiba H, Mittler RS, Gejyo F, Okumura K, Yagita H, Smyth MJ
  • Journal Title: Nature Med 12 Pages: 693-698
  • Peer Reviewed
• [Journal Article] IL-21 enhances tumor-specific CTL induction by anti-DR5 antibody therapy. (2006)
  • Author(s): Smyth MJ, Hayakawa Y, Cretney E, Zerafa N, Sivakumar P, Yagita H, Takeda K
  • Journal Title: J Immunol 176 Pages: 6347-6355
  • Peer Reviewed
• [Journal Article] A novel dendritic cell subset involved in tumor immunosurveillance. (2006)
  • Author(s): Taieb J, Chaput N, Menard C, Apetoh L, Ullrich E, Bonmort M, Pequignot M, Casares N, Terme M, Flament C, Opolon P, Lecluse Y, Metivier G, Tomasello E, Vivier E, Ghiringhelli F, Martin F, Klatzmann D, Poynard T, Tursz T, Raposo G, Yagita H, Ryffel B, Kroemer G, Zitvogel L
  • Journal Title: Nature Med 12 Pages: 214-219
  • Peer Reviewed
• [Journal Article] Sequential activation of NKT cells and NK cells provides effective innate immunotherapy of cancer. (2005)
  • Author(s): Smyth MJ, Wallace ME, Nutt SL, Yagita H, Godfrey DI, Hayakawa Y
  • Journal Title: J Exp Med 201 Pages: 1973-1985
  • Peer Reviewed
• [Journal Article] TWEAK mediates anti-tumor effect of tumor-infiltrating macrophage. (2005)
  • Author(s): Kaduka Y, Takeda K, Nakayama M, Kinoshita K, Yagita H, Okumura K
  • Journal Title: Biochem Biophys Res Commun 331 Pages: 384-390
  • Peer Reviewed
• [Journal Article] Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. (2005)
  • Author(s): Ohigashi Y, Sho M, Yamada Y, Tsurui Y, Hamada K, Ikeda N, Mizuno T, Yoriki R, Kashizuka H, Yane K, Tsushima F, Otsuki N, Yagita H, Azuma M, Nakajima Y
  • Journal Title: Clin Cancer Res 11 Pages: 2947-2953
  • Peer Reviewed
• [Journal Article] IFN-□-mediated negative feedback regulation of NKT cell function by CD94/NKG2. (2005)
  • Author(s): Ota T, Takeda K, Akiba H, Hayakawa Y, Ogasawara K, Ikarashi Y, Miyake S, Wakasugi H, Yamamura T, Kronenberg M, Raulet DH, Kinoshita K, Yagita H, Smyth MJ, Okumura K
  • Journal Title: Blood 106 Pages: 184-192
  • Peer Reviewed
• [Journal Article] Induction of CD70 on dendritic cells through CD40 or TLR stimulation contributes to the development of CD8+ T cell responses in the absence of CD4+ T cells. (2005)
  • Author(s): Bullock TNJ, Yagita H
  • Journal Title: J Immunol 174 Pages: 710-717
  • Peer Reviewed
• [Journal Article] ICOS costimulates invariant NKT cell activation. (2005)
  • Author(s): Kaneda H, Takeda K, Ota T, Kaduka Y, Akiba H, Ikarashi Y, Wakasugi H, Kronenberg M, Kinoshita K, Yagita H, Okumura K
  • Journal Title: Biochem Biophys Res Commun 327 Pages: 201-207
  • Peer Reviewed
• [Presentation] MUC1トランスジェニックマウスにおける抗原特異的制御性T細胞 (2009)
  • Author(s): 杉浦大輔
  • Organizer: 第39回日本免疫学会総会・学術集会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2009-12-03
• [Presentation] CD8□^+ DCs use Tim-3 for phagocytosis of dying cells and cross-presentation (2009)
  • Author(s): 中山勝文
  • Organizer: 第39回日本免疫学会総会・学術集会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2009-12-03
• [Presentation] 消化器癌におけるT細胞Negative Regulatory経路の臨床的意義とその新規治療戦略の可能性 (2009)
  • Author(s): 野見武男
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2009-10-03
• [Presentation] Tim-3は死細胞の貪食およびクロスプレゼンテーションに関与する (2008)
  • Author(s): 中山勝文
  • Organizer: 第38回日本免疫学会総会・学術集会
  • Place of Presentation: 国立京都国際会議場
  • Year and Date: 2008-12-03
• [Presentation] DR5を介した細胞死誘導による原発性硬化性胆管炎様病変の発症 (2008)
  • Author(s): 竹田和由
  • Organizer: 第38回日本免疫学会総会・学術集会
  • Place of Presentation: 国立京都国際会議場
  • Year and Date: 2008-12-01
• [Presentation] ヒト膵癌におけるB7-H3発現の意義と新規治療の可能性 (2008)
  • Author(s): 山戸一郎
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2008-10-29
• [Presentation] 抗体を用いた抗腫瘍免疫の誘導と増強 (2008)
  • Author(s): 八木田秀雄
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2008-10-28
• [Presentation] Jagged2によるNK細胞活性化制御の解析 (2007)
  • Author(s): Kijima Mika
  • Organizer: 第37回日本免疫学会総会・学術集会
  • Place of Presentation: グランドプリンスホテル新高輪
  • Year and Date: 2007-11-21
• [Presentation] NKT細胞活性化と抗体療法の併用による癌治療 (2007)
  • Author(s): 竹田和由
  • Organizer: 第37回日本免疫学会総会・学術集会
  • Place of Presentation: グランドプリンスホテル新高輪
  • Year and Date: 2007-11-20
• [Presentation] Eradication of established tumors by antibody-based therapy combining tumor cell apoptosis and T cell activation (2007)
  • Author(s): Takeda Kazuyoshi
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2007-10-04
• [Presentation] Significance of T cell negative regulatory pathway in human gastrointestinal cancer (2007)
  • Author(s): Sho Masayuki
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2007-10-03
• [Presentation] Eradication of established tumors by a rational antibody-based therapy that combines tumor cell apoptosis and T cell activation (2006)
  • Author(s): Kojima Yuko
  • Organizer: 第36回日本免疫学会総会・学術集会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2006-12-12
• [Presentation] Eradication of established tumors by a rational antibody-based therapy inducing tumor-specific CTLs (2006)
  • Author(s): Takeda Kazuyoshi
  • Organizer: 第36回日本免疫学会総会・学術集会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2006-12-11
• [Presentation] ヒト膵癌におけるPD-L/PD-1 pathwayの意義と新規免疫療法の可能性 (2006)
  • Author(s): 野見武男
  • Organizer: 第65回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2006-09-29
• [Presentation] 難治性消化器癌に対するT細胞Negative Pathway阻害による新規癌免疫療法の有用性 (2006)
  • Author(s): 庄雅之
  • Organizer: 第65回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2006-09-28
• [Presentation] Functional analysis of mouse B7-H3 on T cell response (2005)
  • Author(s): Akiba Hisaya
  • Organizer: 第35回日本免疫学会総会・学術集会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2005-12-13
• [Presentation] T細胞活性化抗体を併用したTRAILレセプター特異的抗体による腫瘍治療 (2005)
  • Author(s): 宇野友康
  • Organizer: 第35回日本免疫学会総会・学術集会
  • Place of Presentation: パシフイコ横浜
  • Year and Date: 2005-12-13
• [Presentation] T cell negative pathway阻害による癌転移抑制効果 (2005)
  • Author(s): 庄雅之
  • Organizer: 第64回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌
  • Year and Date: 2005-09-14
• [Book] 抗体を用いたがんに対する免疫応答の制御 (2009)
  • Author(s): 八木田秀雄
  • Total Pages: 2206-2212
  • Publisher: 羊土社