Analysis of human sarcoma stem cells and memory T stem cells

• Project/Area Number: 16H05451
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Sapporo Medical University
• Principal Investigator: TSUKAHARA Tomohide 札幌医科大学, 医学部, 准教授 (20404634)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2018: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2017: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2016: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000)
• Keywords: 肉腫幹細胞 / 免疫記憶幹細胞 / 代謝 / 癌抗原 / 骨肉腫幹細胞 / がん抗原 / 骨肉腫 / 好気的解糖系 / 免疫学 / 病理学 / 癌

Outline of Final Research Achievements

We identified sarcoma stem cell antigen LIN28B which conferred higher tumor-initiating ability and chemo-resistance to osteosarcoma stem cells. LIN28B suppressed OXPHOS and increased glycolysis dependency in osteosarcoma stem cells. Glycolysis inhibitors could suppress in vitro tumorigenesis of osteosarcoma stem cells.
We also identified a novel human memory T stem cells, "Young Memory T cells". Young memory T cells showed the chemo-resistance, differentiation capacity and superior growth ability upon T cell receptor stimulation. T cells recognizing anti-viral antigen and anti-tumor-associated antigen could be induced from young memory T cells derived from sarcoma patients who received high-dose chemotherapy.

Academic Significance and Societal Importance of the Research Achievements

骨肉腫をはじめとする高い悪性形質を示す肉腫は時に若年者に発症し，化学療法不応例症例の予後は不良である．本研究成果により，解糖系阻害によって腫瘍増殖能が抑制される可能性，抗がん剤の効果が増強される可能性が示唆された．
また免疫記憶幹細胞を制御できれば，がんワクチンやT細胞移入療法による免疫治療の効果をより高められる可能性がある．

Research Products

• [Journal Article] Clonal analysis revealed functional heterogeneity in cancer stem-like cell phenotypes in uterine endometrioid adenocarcinoma. (2019)
  • Author(s): Tabuchi Y, Hirohashi Y, Hashimoto S, Mariya T, Asano T, Ikeo K, Kuroda T, Mizuuchi M, Murai A, Uno S, Kawai N, Kubo T, Nakatsugawa M, Kanaseki T, Tsukahara T, Saito T, Torigoe T.
  • Journal Title: Exp Mol Pathol Volume: 106 Pages: 78-88
  • DOI: 10.1016/j.yexmp.2018.11.013
  • Peer Reviewed / Open Access
• [Journal Article] Identification of novel human leukocyte antigen‐A*11:01‐restricted cytotoxic T‐lymphocyte epitopes derived from osteosarcoma antigen papillomavirus binding factor (2019)
  • Author(s): Li Dongliang、Toji Shingo、Watanabe Kazue、Torigoe Toshihiko、Tsukahara Tomohide
  • Journal Title: Cancer Science Volume: 110 Issue: 4 Pages: 1156-1168
  • DOI: 10.1111/cas.13973
  • Peer Reviewed
• [Journal Article] Cellular stress induces cancer stem-like cells through expression of DNAJB8 by activation of heat shock factor 1 (2018)
  • Author(s): Kusumoto Hiroki、Hirohashi Yoshihiko、Nishizawa Satoshi、Yamashita Masamichi、Yasuda Kazuyo、Murai Aiko、Takaya Akari、Mori Takashi、Kubo Terufumi、Nakatsugawa Munehide、Kanaseki Takayuki、Tsukahara Tomohide、Kondo Toru、Sato Noriyuki、Hara Isao、Torigoe Toshihiko
  • Journal Title: Cancer Science Volume: 109 Issue: 3 Pages: 741-750
  • DOI: 10.1111/cas.13501
  • Peer Reviewed / Open Access
• [Journal Article] The Antigen ASB4 on Cancer Stem Cells Serves as a Target for CTL Immunotherapy of Colorectal Cancer (2018)
  • Author(s): Miyamoto Sho、Kochin Vitaly、Kanaseki Takayuki、Hongo Ayumi、Tokita Serina、Kikuchi Yasuhiro、Takaya Akari、Hirohashi Yoshihiko、Tsukahara Tomohide、Terui Takeshi、Ishitani Kunihiko、Hata Fumitake、Takemasa Ichiro、Miyazaki Akihiro、Hiratsuka Hiroyoshi、Sato Noriyuki、Torigoe Toshihiko
  • Journal Title: Cancer Immunology Research Volume: 6 Issue: 3 Pages: 358-369
  • DOI: 10.1158/2326-6066.cir-17-0518
  • Peer Reviewed / Open Access
• [Journal Article] Long-term survival of a pancreatic cancer patient immunized with an SVN-2B peptide vaccine. (2018)
  • Author(s): Shima H, Kutomi G, Satomi F, Imamura M, Kimura Y, Mizuguchi T, Watanabe K, Takahashi A, Murai A, Tsukahara T, Kanaseki T, Hirohashi Y, Iwayama Y, Tsuruma T, Kameshima H, Sato N, Torigoe T, Takemasa I.
  • Journal Title: Cancer Immunol Immunother. Volume: 67 Issue: 10 Pages: 1603-1609
  • DOI: 10.1007/s00262-018-2217-x
  • Peer Reviewed
• [Journal Article] Differential bronchial epithelial response regulated by ΔNp63: a functional understanding of the epithelial shedding found in asthma (2018)
  • Author(s): Kubo Terufumi、Tsujiwaki Mitsuhiro、Hirohashi Yoshihiko、Tsukahara Tomohide、Kanaseki Takayuki、Nakatsugawa Munehide、Hasegawa Tadashi、Torigoe Toshihiko
  • Journal Title: Laboratory Investigation Volume: 99 Issue: 2 Pages: 158-168
  • DOI: 10.1038/s41374-018-0132-6
  • Peer Reviewed
• [Journal Article] Development of a T-cell receptor multimer with high avidity for detecting a naturally presented tumor-associated antigen on osteosarcoma cells (2018)
  • Author(s): Watanabe Kazue、Tsukahara Tomohide、Toji Shingo、Saitoh Shogo、Hirohashi Yoshihiko、Nakatsugawa Munehide、Kubo Terufumi、Kanaseki Takayuki、Kameshima Hidekazu、Terui Takeshi、Sato Noriyuki、Torigoe Toshihiko
  • Journal Title: Cancer Science Volume: 110 Issue: 1 Pages: 40-51
  • DOI: 10.1111/cas.13854
  • Peer Reviewed
• [Journal Article] 次世代がんペプチドワクチン療法の開発 (2017)
  • Author(s): 塚原智英，廣橋良彦，鳥越俊彦.
  • Journal Title: 日本臨牀 Volume: 75 Pages: 275-279
• [Journal Article] がん幹細胞の単離と免疫治療に向けた標的抗原の同定． (2017)
  • Author(s): 27.宮本昇，金関貴幸，廣橋良彦，塚原智英，菊池泰弘，佐藤昇志，鳥越俊彦．
  • Journal Title: 日本臨床免疫学会雑誌 Volume: 17 Pages: 40-47
  • NAID: 130005665568
• [Journal Article] Cancer-associated oxidoreductase ERO1-α promotes immune escape through up-regulation of PD-L1 in human breast cancer. (2017)
  • Author(s): Tanaka T, Kutomi G, Kajiwara T, Kukita K, Kochin V, Kanaseki T, Tsukahara T, Hirohashi Y, Torigoe T, Okamoto Y, Hirata K, Sato N, Tamura Y.
  • Journal Title: Oncotarget Volume: 2016 Issue: 15 Pages: 24706-24718
  • DOI: 10.18632/oncotarget.14960
  • NAID: 120006219870
  • Peer Reviewed / Open Access
• [Journal Article] The future of immunotherapy for sarcoma. (2016)
  • Author(s): Tsukahara T , Emori M, Murata K, Mizushima E, Shibayama Y, Kubo T, Kanaseki T, Hirohashi Y, Yamashita T, Sato N, Torigoe T.
  • Journal Title: Expert Opin Biol Ther Volume: 16 Pages: 1049-1057
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Peptide vaccination therapy: Towards the next generation (2016)
  • Author(s): Tsukahara T , Hirohashi Y, Kanaseki T, Nakatsugawa M, Kubo T, Sato N, Torigoe T. Peptide vaccination therapy: Towards the next generation.
  • Journal Title: Pathol Int Volume: 66 Pages: 547-553
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Identification of a novel human memory T cell population with the characteristics of stem-like chemo-resistance (2016)
  • Author(s): Murata K, Tsukahara T, Emori M, Shibayama Y, Mizushima E, Matsumiya H, Yamashita K, Kaya M, Hirohashi Y, Kanaseki T, Kubo T, Himi T, Ichimiya S, Yamashita T, Sato N, Torigoe T
  • Journal Title: OncoImmunology Volume: 5
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Cancer-associated oxidoreductase ERO1-α drives the production of VEGF via oxidative protein folding and regulating the mRNA level (2016)
  • Author(s): Tanaka T, Kutomi G, Kajiwara T, Kukita K, Kochin V, Kanaseki T, Tsukahara T, Hirohashi Y, Torigoe T, Okamoto Y, Hirata K, Sato N, Tamura Y.
  • Journal Title: Br J Cancer Volume: 114 Pages: 1227-1234
  • NAID: 120006219952
  • Peer Reviewed
• [Journal Article] Establishment and analysis of cancer stem-like and non-cancer stem-like cells from the human colon cancer cell line SW480 (2016)
  • Author(s): Akari Takaya, Yoshihiko Hirohashi, et al.
  • Journal Title: PLOS One Volume: 14;11(7) Issue: 7 Pages: e0158903-e0158903
  • DOI: 10.1371/journal.pone.0158903
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Plasticity of lung cancer stem-like cells is regulated by the transcription factor HOXA5 that is induced by oxidative stress (2016)
  • Author(s): Hiroshi Saijo, Yoshihiko Hirohashi, et al.
  • Journal Title: Oncotarget Volume: 2;7(31) Issue: 31 Pages: 50043-50056
  • DOI: 10.18632/oncotarget.10571
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hypoxia augments MHC class I antigen presentation via facilitation of ERO1-α-mediated oxidative folding in murine tumor cells. (2016)
  • Author(s): Kajiwara T, Tanaka T, Kukita K, Kutomi G, Saito K, Okuya K, Takaya A, Kochin V, Kanaseki T, Tsukahara T, Hirohashi Y, Torigoe T, Hirata K, Sato N, Tamura Y.
  • Journal Title: Eur J Immunol. Volume: 46 Pages: 2842-2851
  • Peer Reviewed
• [Presentation] これでわかる！癌と免疫 (2018)
  • Author(s): 塚原 智英
  • Organizer: 第91回日本整形外科学会学術総会
• [Presentation] 肉腫免疫療法の基礎と応用 (2018)
  • Author(s): 塚原 智英
  • Organizer: 第107回日本病理学会総会
• [Presentation] 骨肉腫幹細胞抗原LIN28Bを標的とした解糖代謝制御と免疫治療開発 (2018)
  • Author(s): 水島 衣美、塚原 智英、他
  • Organizer: 第22回日本がん免疫学会総会
• [Presentation] 骨肉腫幹細胞はLIN28Bを介した好気的解糖に依存した代謝メカニズムを有する (2018)
  • Author(s): 水島 衣美、塚原 智英、他
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 骨・軟部肉腫に対する癌幹細胞抗原DNAJB8を標的としたHLA/ペプチド複合体特異的人工抗体の開発 (2018)
  • Author(s): 塚原 智英
  • Organizer: 第33回日本整形外科学会基礎学術集会
• [Presentation] 免疫チェックポイント阻害剤のエビデンスレビュー (2018)
  • Author(s): 塚原 智英
  • Organizer: 第46回日本臨床免疫学会総会
• [Presentation] Peptide vaccination could elicit strong immune responses and be re-boosted by anti-PD1 therapy in a sarcoma patient (2017)
  • Author(s): 塚原智英、亀嶋秀和、照井健、渡邉一絵、鳥越俊彦
  • Organizer: 第21回日本がん免疫学会総会
• [Presentation] Identification of a novel human T cell population with the characteristics of stem-like chemo-resistance (2017)
  • Author(s): Tsukahara T, Murata K, Shibayama Y, Emori M, Mizushima E, Tadano H, Torigoe T.
  • Organizer: THIRD CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference
  • Int'l Joint Research
• [Presentation] Identification of a human novel memory T cell population with the characteristics of chemo-resistance. (2016)
  • Author(s): 塚原 智英
  • Organizer: 第20回日本がん免疫学会総会
  • Place of Presentation: 大阪国際交流センター（大阪市）
• [Book] Osteosarcoma - A Multidisciplinary Approach to Treatment (2016)
  • Author(s): 5.Tsukahara T, Wada T. Immunotherapy for osteosarcoma
  • Total Pages: 270
  • Publisher: Springer Japan KK
• [Patent(Industrial Property Rights)] がん幹細胞特異的抗体 (2018)
  • Inventor(s): 塚原智英，鳥越俊彦
  • Industrial Property Rights Holder: 塚原智英，鳥越俊彦
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-189834
  • Filing Date: 2018