がんに対する免疫賦活化抗体療法の開発

2012 年度 研究成果報告書

• 研究課題/領域番号: 22240089
• 研究種目: 基盤研究(A)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 腫瘍免疫学
• 研究機関: 順天堂大学
• 研究代表者: 八木田 秀雄 順天堂大学, 医学部, 先任准教授 (30182306)
• 研究期間 (年度): 2010 – 2012
• キーワード: がん / 免疫 / 抗体療法 / キラーT細胞 / 4-1BB / CD27 / CTLA-4 / PD-1 / TIM-3

研究概要

がん細胞に免疫原性細胞死を惹起する新たな手法を開発した。また、がんに対する免疫応答を増強する経路(4-1BB, CD27, Notch2 など)及び、逆に抑制する経路(CTLA-4, PD-1, TIM-3など)を明らかにし、それらに対する活性化抗体あるいは阻害抗体を用いて、標準的な抗がん剤や放射線あるいはがん細胞を標的とした抗体療法によって惹起されるがんに対する免疫応答の新たな増強法を開発した。

研究成果

• [雑誌論文] Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumor effect in vivo (2013)
  • 著者名/発表者名: Yasuda S, Sho M, Yamato I, Yoshiji H, Wakatsuki K, Nishiwada S, Yagita H, Nakajima Y
  • 雑誌名: Clin Exp Immunol 巻: 172 ページ: 500-506
  • DOI: DOI:10.1111/cei.12069
  • 査読あり
• [雑誌論文] Host immunity contributes to the anti-melanoma activity of BRAF inhibitors (2013)
  • 著者名/発表者名: Knight DA, Ngiow SF, Li M, Parmenter T, Mok S, Cass A, Haynes NM, Kinross K, Yagita H, Koya RC, Greber TG, Ribas A, McArthur GA, Smyth MJ
  • 雑誌名: J Cin Inves 巻: 123 ページ: 1371-1381
  • DOI: DOI:10.1172/JCI66236
  • 査読あり
• [雑誌論文] Combined blockade of TIM-3 and TIM-4 augments cancer vaccine efficacy against established melanomas (2013)
  • 著者名/発表者名: Baghdadi M, Nagao H, Yoshiyama H, Akiba H, Yagita H, Dosaka-Akita H, Jinushi M
  • 雑誌名: Cancer Immunol Immunother 巻: 62 ページ: 629-637
  • DOI: DOI:10.1007/s00262-012-1371-9
  • 査読あり
• [雑誌論文] The TWEAK receptor Fn14 is a therapeutic target in melanoma: Immunotoxins targeting Fn14 receptor for malignant melanoma treatment (2013)
  • 著者名/発表者名: Zhou H, Ekmekcioglu S, Marks JW, Mohamedali KA, Asrani K, Phillips KK, Brown SA, Cheng E, Weiss MB,Hittelman WN, Tran NL, Yagita H, Winkles JA, Rosenblum MG
  • 雑誌名: J Invest Dermatol 巻: 133 ページ: 1052-1062
  • DOI: DOI:10.1038/jid.2-12.402
  • 査読あり
• [雑誌論文] Durable adoptive immunotherapy for leukemia produced by manipulation of multiple regulatory pathways of CD8+ T cell tolerance (2013)
  • 著者名/発表者名: Berrien-Elliott MM, Jackson SR, Meyer JM, Rouskey CJ, Nguyen TL, Yagita H, Greenberg P, Dipaolo RJ, Teague RM
  • 雑誌名: Cancer Res 巻: 73 ページ: 605-616
  • DOI: DOI:10.1158/0008-5472.CAN-12-2179
  • 査読あり
• [雑誌論文] PD-1 blockade enhances T cell migration to tumors by elevating IFN-γ inducible chemokines (2012)
  • 著者名/発表者名: Peng W, Liu C, Xu C, Lou Y, Chen J, Yang Y, Yagita H, Overwijk WW, Lizee G, Radvanyi L, Hwu P
  • 雑誌名: Cancer Res 巻: 72 ページ: 5209-5218
  • DOI: DOI:10.1158/0008-5472.CAN-12-2179
  • 査読あり
• [雑誌論文] Polyfunctional CD4+ T cells are essential for eradicating advanced B-cell lymphoma after chemotherapy (2012)
  • 著者名/発表者名: Ding ZC, Huang L, Blazar BR, Yagita H, Mellor AL, Munn DH, Zhou G
  • 雑誌名: Blood 巻: 120 ページ: 2229-2239
  • DOI: DOI:10.1182/blood-2011-12-398321
  • 査読あり
• [雑誌論文] Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1 (2012)
  • 著者名/発表者名: Chiba S, Baghdadi M, Akiba H, Yoshiyama H, Kinoshita I, Dosaka-Akita H, Fujioka Y, Ohba Y, Gorman JV, Colganb JD, Hirashima M, Uede T, Takaoka A, Yagita H, Jinushi M
  • 雑誌名: Nat Immunol 巻: 13 ページ: 832-842
  • DOI: DOI:10.1038/ni.2376
  • 査読あり
• [雑誌論文] The CD4+ T-cell help signal is transmitted from APC to CD8+ T-cells via CD27-CD70 interactions (2012)
  • 著者名/発表者名: Feau S, Garcia Z, Arens R, Yagita H, Borst J, Schoenberger SP
  • 雑誌名: Nat Commun 巻: 3 ページ: 948
  • DOI: DOI:10.1038/ncomms1948
  • 査読あり
• [雑誌論文] Radiotherapy promotes tumor-specific effector CD8+ T cells via dendritic cell activation (2012)
  • 著者名/発表者名: Gupta A, Probst HC, Vuong V, Landshammer A, Muth S, Yagita H, Schwendener R, Pruschy M, Knuth A, van den Broek M
  • 雑誌名: J Immunol 巻: 189 ページ: 558-566
  • DOI: DOI: 10.4049/jimmunol.1200563
  • 査読あり
• [雑誌論文] Radiotherapy increases the permissiveness of established mammary tumors to rejection by immunomodulatory antibodies (2012)
  • 著者名/発表者名: Verbrugge I, Hagekyriakou J, Sharp LL, Galli M, West AC, McLaughlin NM, Duret H, Yagita H, Johnstone RW, Smyth MJ, Haynes NM
  • 雑誌名: Cancer Res 巻: 72 ページ: 3163-3174
  • DOI: DOI:10.1158/0008-5472.CAN-12-0210
  • 査読あり
• [雑誌論文] Cancer-induced immunosuppression: IL-18-elicited immunoablative NK cells (2012)
  • 著者名/発表者名: Terme M, Ullrich E, Aymeric L, Meinhardt K, Coudert J, Desbois M, Ghiringhelli F, Viaud S, Ryffel B, Yagita H, Chen L, Mecheri S, Kaplanski G, Prevost-Blondel A, Kato M, Schultze JL, Tartour E, Kroemer G, Degli-Esposti M, Chaput N, Zitvogel L
  • 雑誌名: Cancer Res 巻: 72 ページ: 2757-2767
  • DOI: DOI:10.1158/0008-5472.CAN-11-3379
  • 査読あり
• [雑誌論文] Induction of pro-apoptotic antibodies to triple negative breast cancer by vaccination with TRAIL death receptor DR5 DNA (2012)
  • 著者名/発表者名: Piechocki MP, Wu GS, Jones RF, Jacob JB, Gibson H, Ethier SP, Abrams1 J, Yagita H, Venuprasad K, Wei WZ
  • 雑誌名: Int J Cancer 巻: 131 ページ: 2562-2572
  • DOI: DOI:10.1002/ijc.27534
  • 査読あり
• [雑誌論文] ATM-mediated DNA damage signals mediate immune escape through integrin αVβ3-dependent mechanisms (2012)
  • 著者名/発表者名: Jinushi M, Chiba S, Baghdadi M, Kinoshita I, Dosaka-Akita H, Yoshiyama H, Yagita H, Uede T, Takaoka A
  • 雑誌名: Cancer Res 巻: 72 ページ: 56-65
  • DOI: DOI:10.1158/0008-5472.CAN-11-2028
  • 査読あり
• [雑誌論文] Aging-associated B7-DC(+) B cells enhance anti-tumor immunity via Th1 and Th17 induction (2012)
  • 著者名/発表者名: Tomihara K, Shin T, Hurez VJ, Yagita H, Pardoll DM, Zhang B, Curiel TJ, Shin T
  • 雑誌名: Aging Cell 巻: 11 ページ: 128-138
  • DOI: DOI:10.1111/j.1474-9726.2011.00764.x
  • 査読あり
• [雑誌論文] Importin β1 protein-mediated nuclear localization of death receptor 5 (DR5) limits DR5/tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced cell death of human tumor cells (2011)
  • 著者名/発表者名: Kojima Y, Nakayama M, Nishina T, Nakano H, Koyanagi M, Takeda K, Okumura K, Yagita H
  • 雑誌名: J Biol Chem 巻: 286 ページ: 43383-43393
  • DOI: DOI:10.1074/jbc.M111.309377
  • 査読あり
• [雑誌論文] Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells (2011)
  • 著者名/発表者名: Jinushi M, Chiba S, Yoshiyama H, Masutomi K, Kinoshita I, Dosaka H, Yagita H, Takaoka A, Tahara H
  • 雑誌名: Proc Natl Acad Sci USA 巻: 108 ページ: 12425-12430
  • DOI: DOI:10.1073/pnas.1106645108
  • 査読あり
• [雑誌論文] IL-18 induces PD-1-dependent immunosuppression in cancer (2011)
  • 著者名/発表者名: Terme M, Ullrich E, Aymeric L, Meinhardt K, Desbois M, Delahaye NF, Viaud S, Ryffel B, Yagita H, Kaplanski G, Prevost-Blondel A, Kato M, Schultze JL, Tartour E, Kroemer G, Chaput N, Zitvogel L
  • 雑誌名: Cancer Res 巻: 71 ページ: 5412-5422
  • DOI: DOI:10.1158/0008-5472.CAN-11-0993
  • 査読あり
• [雑誌論文] Development and characterization of a potent immunoconjugate targeting the Fn14 receptor on solid tumor cells (2011)
  • 著者名/発表者名: Zhou H, Marks JW, Hittelman WN, Yagita H, Cheung LH, Rosenblum MG, Winkles JA
  • 雑誌名: Mol Cancer Ther 巻: 10 ページ: 1276-1288
  • DOI: DOI:0.1158/1535-7163.MCT-11-0161
  • 査読あり
• [雑誌論文] Combination of lentivector immunization and low dose chemotherapy or PD-1/PD-L1 blocking primes self-reactive T cells and induces anti-tumor immunity (2011)
  • 著者名/発表者名: Sierro SR, Donda A, Perret R, Guillaume P, Yagita H, Levy F, Romero P
  • 雑誌名: Eur J Immunol 巻: 41 ページ: 2217-2228
  • DOI: DOI:10.1002/eji.201041235
  • 査読あり
• [雑誌論文] TLR2-dependent induction of IL-10 and Foxp3+CD25+CD4+ regulatory T cells prevents effective anti-tumor immunity induced by Pam2 lipopeptides in vivo (2011)
  • 著者名/発表者名: Yamazaki S, Okada K, Maruyama A, Matsumoto M, Yagita H, Seya T
  • 雑誌名: PLoS One 巻: 6(4) ページ: e18833
  • DOI: DOI:10.1371/journal.pone.0018833
  • 査読あり
• [雑誌論文] Anti-ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti-PD-1 or anti-CD137 mAb therapy (2011)
  • 著者名/発表者名: Stagg J, Loi S, Divisekera U, Ngiow SF, Duret H, Yagita H, Teng MW, Smyth MJ
  • 雑誌名: Proc Natl Acad Sci USA 巻: 108 ページ: 7142-7147
  • DOI: DOI:10.1073/pnas.1016569108
  • 査読あり
• [雑誌論文] FOXO3 programs tumor-associated DCs to become tolerogenic in human and murine prostate cancer (2011)
  • 著者名/発表者名: Watkins SK, Zhu Z, Riboldi E, Shafer-Weaver KA, Stagliano KE, Sklavos MM, Ambs S, Yagita H, Hurwitz AA
  • 雑誌名: J Clin Invest 巻: 121 ページ: 1361-1372
  • DOI: DOI:10.1172/JCI44325
  • 査読あり
• [雑誌論文] Anti-TIM3 antibody promotes T cell IFN-γ-mediated anti-tumor immunity and suppresses established tumors (2011)
  • 著者名/発表者名: Ngiow SF, von Scheidt B, Akiba H, Yagita H, Teng MW, Smyth MJ
  • 雑誌名: Cancer Res 巻: 71 ページ: 3540-3551
  • DOI: DOI: 10.1158/0008-5472.CAN-11-0096
  • 査読あり
• [雑誌論文] Epigenetic modulation enhances the therapeutic effect of anti-IL13Ralpha2 antibody in human mesothelioma xenografts (2011)
  • 著者名/発表者名: Takenouchi M, Hirai S, Sakuragi N, Yagita H, Hamada H, Kato K
  • 雑誌名: Clin Cancer Res 巻: 17 ページ: 2819-2829
  • DOI: DOI:10.1158/1078-0432.CCR-10-2986
  • 査読あり
• [雑誌論文] Anti-tumor activities and on-target toxicities mediated by TRAIL receptor agonist following co-treatment with panobinostat (2011)
  • 著者名/発表者名: Martin BP, J Frew A, Bots M, Fox S, Long F, Takeda K, Yagita H, Atadja P, Smyth MJ, Johnstone RW
  • 雑誌名: Int J Cancer 巻: 128 ページ: 2735-2747
  • DOI: DOI:10.1002/ijc.25594
  • 査読あり
• [雑誌論文] Therapeutic potential of the TWEAK/Fn14 pathway in intractable gastrointestinal cancer (2011)
  • 著者名/発表者名: Yoriki R, Akashi S, Sho M, Nomi T, Yamato I, Hotta K, Takayama T, Matsumoto S, Wakatsuki K, Migita K, Yagita H, Nakajima Y
  • 雑誌名: Exp Ther Med 巻: 2 ページ: 103-108
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/22977477
  • 査読あり
• [雑誌論文] Blockade of programmed death-1 pathway rescues the effector function of tumor-infiltrating T cells and enhances the antitumor efficacy of lentivector immunization (2010)
  • 著者名/発表者名: Zhou Q, Xiao H, Liu Y, Peng Y, Hong Y, Yagita H, Chandler P, Munn DH, Mellor A, Fu N, He Y
  • 雑誌名: J Immunol 巻: 185 ページ: 5082-5092
  • DOI: DOI:10.4049/jimmunol.1001821
  • 査読あり
• [雑誌論文] Spatiotemporal basis of CTLA-4 costimulatory molecule-mediated negative regulation of T cell activation (2010)
  • 著者名/発表者名: Yokosuka T, Kobayashi W, Takamatsu M, Sakata-Sogawa K, Zeng H, Hashimoto-Tane A, Yagita H, Tokunaga M, Saito T
  • 雑誌名: Immunity 巻: 33 ページ: 326-339
  • DOI: DOI:10.1016/j.immuni.2010.09.006
  • 査読あり
• [雑誌論文] Control of established melanoma by CD27 stimulation is associated with enhanced effector function and persistence,and reduced PD-1 expression of tumor infiltrating CD8+ T cells (2010)
  • 著者名/発表者名: Roberts DJ, Franklin NA, Kingeter LM, Yagita H, Tutt AL, Glennie MJ, Bullock TN
  • 雑誌名: J Immunother 巻: 33 ページ: 769-779
  • DOI: DOI:10.1097/CJI.0b013e3181ee238f
  • 査読あり
• [雑誌論文] Peptide vaccine induces enhanced tumor growth associated with apoptosis induction in CD8+ T cells (2010)
  • 著者名/発表者名: Muraoka D, Kato T, Wang L, Maeda Y, Noguchi T, Harada N, Takeda K, Yagita H, Guillaume P, Luescher I, Old LJ, Shiku H, Nishikawa H
  • 雑誌名: J Immunol 巻: 185 ページ: 3768-3776
  • DOI: DOI:10.4049/jimmunol.0903649
  • 査読あり
• [雑誌論文] Darcy PK, Smyth MJ: CD11c+ dendritic cells and B cells contribute to the tumoricidal activity of anti-DR5 antibody therapy in established tumors (2010)
  • 著者名/発表者名: Haynes NM, Hawkins ED, Li M, McLaughlin NM, Hammerling GJ, Schwendener R, Winoto A, Wensky A, Yagita H, Takeda K, Kershaw MH
  • 雑誌名: J Immunol 巻: 185 ページ: 532-541
  • DOI: DOI:10.4049/jimmunol.0903624
  • 査読あり
• [雑誌論文] Combination therapy of established tumors by antibodies targeting immune activating and suppressing molecules (2010)
  • 著者名/発表者名: Takeda K, Kojima Y, Uno T, Hayakawa Y, Teng MWL, Yoshizawa H, Yagita H, Geyjo F, Okumura K, Smyth MJ
  • 雑誌名: J Immunol 巻: 184 ページ: 5493-5501
  • DOI: DOI:10.4049/jimmunol.0903033
  • 査読あり
• [雑誌論文] Notch2 signaling is required for potent antitumor immunity in vivo (2010)
  • 著者名/発表者名: Sugimoto K, Maekawa Y, Kitamura A, Nishida J, Koyanagi A, Yagita H, Kojima H, Chiba S, Shimada M, Yasutomo K
  • 雑誌名: J Immunol 巻: 184 ページ: 4673-4678
  • DOI: DOI:10.4049/jimmunol.0903661
  • 査読あり
• [雑誌論文] Optimized combination therapy using bortezomib, TRAIL and TLR agonists in established breast tumors (2010)
  • 著者名/発表者名: Lee S, Yagita H, Sayers TJ, Celis E
  • 雑誌名: Cancer Immunol Immunother 巻: 59 ページ: 1073-1081
  • DOI: DOI:10.1007/s00262-010-0834-0
  • 査読あり
• [雑誌論文] lockade of delta-like ligand 4 signaling inhibits both growth and angiogenesis of pancreatic cancer (2010)
  • 著者名/発表者名: Oishi H, Sunamura M. Egawa S, Motoi F, Unno M, Furukawa T, Habib NA, Yagita H
  • 雑誌名: Pancreas 巻: 39 ページ: 897-903
  • DOI: DOI:10.1097/MPA.0b013e3181ce7185
  • 査読あり
• [雑誌論文] Anti-tumor effects of depleting and non-depleting anti-CD27 monoclonal antibodies in immune-competent mice (2010)
  • 著者名/発表者名: Sakanishi T, Yagita H
  • 雑誌名: Biochem Biophys Res Commun 巻: 393 ページ: 829-835
  • DOI: DOI:10.1016/j.bbrc.2010.02.092
  • 査読あり
• [雑誌論文] PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors (2010)
  • 著者名/発表者名: Curran MA, Montalvo W, Yagita H, Allison JP
  • 雑誌名: Proc Natl Acad Sci USA 巻: 107 ページ: 4275-4280
  • DOI: DOI:10.1016/j.bbrc.2010.02.092
  • 査読あり
• [雑誌論文] Tumor-reactive CD4+ T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts (2010)
  • 著者名/発表者名: Quezada SA, Simpson TR, Peggs KS, Merghoub T, Vider J, Fan X, Blasberg R, Yagita H, Muranski P, Antony PA, Restifo NP, Allison JP
  • 雑誌名: J Exp Med 巻: 207 ページ: 637-650
  • DOI: DOI:10.1084/jem.20091918
  • 査読あり
• [雑誌論文] DNAM-1/CD155 interactions promote cytokine NK cell-mediated suppression of poorly immunogenic melanoma metastasis (2010)
  • 著者名/発表者名: Chan CJ, Andrew DM, McLaughlin NM, Yagita H, Gilfillan S, Colonna M, Smyth MJ
  • 雑誌名: J Immunol 巻: 184 ページ: 902-911
  • DOI: DOI:10.4049/jimmunol.0903225
  • 査読あり