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Rational design of the next-generation peptide immunotherapy which exploits tumor endothelial cells as an APC.

Research Project

Project/Area Number 19K07775
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 50020:Tumor diagnostics and therapeutics-related
Research InstitutionKochi University

Principal Investigator

Udaka Keiko  高知大学, 教育研究部医療学系基礎医学部門, 教授 (40263066)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
KeywordsMHC分子 / ペプチド / 腫瘍免疫 / Th / 機械学習 / 自己免疫疾患 / 血管内皮細胞 / 抗原提示 / CTL / クロスプレゼンテーション / T細胞 / 腫瘍 / 浸潤 / 抗原特異的 / HLA class II / peptide / Immunotherapy
Outline of Research at the Start

腫瘍血管内皮細胞(EC)の抗原提示能を活かして、腫瘍組織に腫瘍抗原特異的T細胞の浸潤を促す免疫療法を開発する。本研究では、以下の3つを達成したい。
1)機械学習を用いた、HLA class II-結合性ペプチドの予想platformの作製
2)ペプチド免疫によるTh、CTL誘導効率を高めるため、担体Mとペプチドおよびアジュバントを混ぜて皮内注射する方法を、Mなしの免疫と比較する。
3)人のペプチド免疫療法で誘導されがちな、アミノ酸変異のない腫瘍抗原に対するCTLについて、in vivoにおける抗腫瘍活性を検討する。また、より高い抗腫瘍活性を誘導する免疫法を開発する。

Outline of Final Research Achievements

We have delineated an antigen-specific mechanism of T-cell infiltration into tumor tissues where endothelial cells act as antigen presenting cells (APCs). Tumor endothelial cells (tECs) present tumor antigen peptides in the context of MHC class I and class II molecules. A next-generation peptide immunotherapy which induces tumor-specific Th cells along with CTLs exhibited prominent anti-tumor responses. We further identified that a compound U2317 enhances cross presentation of tumor antigens by tECs. Since the performance of currently available platforms to predict MHC class II-binding peptides are quite limited we have first developed a method to measure MHC class II-peptide interactions accurately and then developed a computational platform to predict MHC class II-binding peptides. The resultant platforms could be used to identify epitope peptides for anti-tumor immunotherapy and investigation of autoimmune diseases.

Academic Significance and Societal Importance of the Research Achievements

これまで治療効果に限界があった悪性腫瘍に対するペプチド免疫療法に、新たに明らかにした腫瘍抗原特異的なT細胞の浸潤機構を活用して治療効果を画期的に高め、動物実験では完治例も出る次世代ワクチンを開発した。この原理を利用すれば、自己免疫疾患の原因解明や制御のみならず、不用な非腫瘍性細胞を積極的に除去する新規治療法の開発も可能となる。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (33 results)

All 2022 2021 2020 2019 Other

All Journal Article (6 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 6 results,  Open Access: 3 results) Presentation (24 results) (of which Invited: 4 results) Book (2 results) Remarks (1 results)

  • [Journal Article] Identification of Neoantigens in Two Murine Gastric Cancer Cell Lines Leading to the Neoantigen-Based Immunotherapy2022

    • Author(s)
      Koji Nagaoka, Changbo Sun, Yukari Kobayashi, Takayuki Kanaseki, Serina Tokita, Toshihiro Komatsu, Kazuhiro Maejima, Junichiro Futami, Sachiyo Nomura, Keiko Udaka, Hidewaki Nakagawa, Toshihiko Torigoe, Kazuhiro Kakimi
    • Journal Title

      Cancers

      Volume: 14 Issue: 1 Pages: 106-106

    • DOI

      10.3390/cancers14010106

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of mouse helper epitopes for WT1-specific CD4+ T cells2021

    • Author(s)
      Nakajima Hiroko、Nakata Jun、Imafuku Kanako、Hayashibara Hiromu、Isokawa Kazuki、Udaka Keiko、Fujiki Fumihiro、Morimoto Soyoko、Hasegawa Kana、Hosen Naoki、Hashii Yoshiko、Nishida Sumiyuki、Tsuboi Akihiro、Oka Yoshihiro、Oji Yusuke、Sogo Shinji、Sugiyama Haruo
    • Journal Title

      Cancer Immunology, Immunotherapy

      Volume: 70 Issue: 11 Pages: 3323-3335

    • DOI

      10.1007/s00262-021-03003-5

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Carboxylated polyamidoamine dendron-bearing lipid-based assemblies for precise control of intracellular fate of cargo and induction of antigen-specific immune responses.2020

    • Author(s)
      Eiji Yuba , Yoshikatsu Sugahara, Yuta Yoshizaki, Takeyuki Shimizu, Michiyuki Kasai, Keiko Udaka, Kenji Kono
    • Journal Title

      Biomater Sci

      Volume: 9 Issue: 8 Pages: 3076-3089

    • DOI

      10.1039/d0bm01813a

    • NAID

      120007026014

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] A phase I study of multi-HLA-binding peptides derived from heat shock protein 70/glypican-3 and a novel combination adjuvant of hLAG-3Ig and Poly-ICLC for patients with metastatic gastrointestinal cancers: YNP01 trial.2020

    • Author(s)
      Masao;Nakajima, Shoichi, Hazama; Koji;Tamada. Nobuaki;Suzuki.Hiroaki;Nagano
    • Journal Title

      Cancer Immunology, Immunotherapy

      Volume: 5 Issue: 8 Pages: 5-10

    • DOI

      10.1007/s00262-020-02518-7

    • Related Report
      2020 Research-status Report 2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Development of a novel monoclonal antibody that binds to most HLA-A allomorphs in a conformation-dependent yet peptide-promiscuous fashion2020

    • Author(s)
      Toshihiro Komatsu, Takeyuki Shimizu, Makoto Kanoh, Tomoya Miyakawa, Yoko Satta, Yoshiki Yasukochi, Rika Fujimoto, Motoki Tada, Kaori Machida, Sayo Kataoka, Keiko Udaka
    • Journal Title

      Immunogenetics

      Volume: 72 Issue: 3 Pages: 143-153

    • DOI

      10.1007/s00251-020-01154-w

    • Related Report
      2020 Research-status Report 2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Identification of a Promiscuous Epitope Peptide Derived From HSP70.2019

    • Author(s)
      Matsui H, Hazama S, Tamada K, Udaka K, Irie A, Nishimura Y, Miyakawa T, Doi S, Nakajima M, Kanekiyo S, Tokumitsu Y, Shindo Y, Tomochika S, Yoshida S, Iida M, Suzuki N, Takeda S, Yamamoto S, Yoshino S, Ueno T, Nagano H
    • Journal Title

      J Immunother

      Volume: 42 Issue: 7 Pages: 244-250

    • DOI

      10.1097/cji.0000000000000274

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] The infiltration of tumor-specific regulatory T cells requires MHC class Ⅱ-expression on endothelial cells2021

    • Author(s)
      UDAKA Keiko, KOMATSU Toshihiro, SHIMIZU Takeyuki, KUBOTA Yoshiaki
    • Organizer
      第25回日本がん免疫学会総会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Efficient induction of effector T cells by peptide immunization in a micelle formula2021

    • Author(s)
      .SHIMIZU Takeyuki, KASAI Michiyuki, SAKAGUCHI Naoki, YAMASHITA Yoshiko, ONOUE Kousuke, TANAKA Yuki, IWASE Youichiro, UDAKA Keiko
    • Organizer
      第25回日本がん免疫学会総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Construction of a platform to predict HLA-DRB1*04:05-binding peptides trained by query learning2021

    • Author(s)
      Keiko Udaka, Morito Chabata
    • Organizer
      第50回日本免疫学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Induction of T cell responses by peptide immunization delivered by a novel pyro-drive jet injector,Actranza2021

    • Author(s)
      Toshihiro Komatsu, Michiyuki Kasai, Yuko Sakaguchi, Naoki Sakaguchi, Keiko Udaka
    • Organizer
      第50回日本免疫学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] SARS-CoV-2 spike L452R and Y453F variants confer escape from immunodominant HLA-A24-restricted T cell recognition2021

    • Author(s)
      Chihiro Motozono, Hiroshi Hamana, Keiko Udaka, Hiroyuki Kishi, Takamasa Ueno
    • Organizer
      第50回日本免疫学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Optimization of culture conditions and method of detection to monitor T cells specific for HLA-peptides in PBMCs2020

    • Author(s)
      宇高恵子、中田あさみ、町田香織、小松利広、清水健之
    • Organizer
      第24回日本がん免疫学会総会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] 血管内皮細胞の抗原提示機能を活かした癌のペプチド免疫療法2020

    • Author(s)
      宇高恵子
    • Organizer
      第50回 日本皮膚免疫アレルギー学会総会学術大会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] ホルモン療法抵抗性前立がんに発現される腫瘍抗原SNに対するCD8+T細胞株の樹立2019

    • Author(s)
      花立裕充、笠井道之、小松利広、岸裕幸、土肥俊、宇高恵子
    • Organizer
      第18回四国免疫フォーラム
    • Related Report
      2019 Research-status Report
  • [Presentation] Antigen specific infiltration of T cells guided by tumor endothelial cells (国際シンポジウム)2019

    • Author(s)
      Udaka K, Komatsu T, Noguchi Y
    • Organizer
      第23回日本がん免疫学会総会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] ネオアンチゲン特異的CTLによる抗腫瘍効果の比較2019

    • Author(s)
      長岡孝治、細井亮宏、孫 長博、小松利広、宇高恵子、垣見和宏
    • Organizer
      第23回日本がん免疫学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] Promiscuous binding of HLA-DRB1*04:05-binding peptides to other HLA class II molecules2019

    • Author(s)
      有馬直輝、宇高恵子、池 成基、梅村孟司、笠島理加、小松利広、山下慶子、宮川知也、土肥俊、横山彰仁、北岡裕章
    • Organizer
      第23回日本がん免疫学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] Cross-presentation by ECs augments anti-tumor responses in targeting a natural tumor antigen in prostate cancer2019

    • Author(s)
      山本快亮、笠井道之、小松利広、花立裕充、坂口奈央樹、浜名 洋、岸 裕幸、土肥俊、宇高恵子
    • Organizer
      第23回日本がん免疫学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] HLA-ペプチド結合予測腫瘍のネオアンチゲンでの評価2019

    • Author(s)
      尾上広祐、山下慶子、Brandon Malone、田中雄希、町田香織、宇高恵子
    • Organizer
      第23回日本がん免疫学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] Construction of a platform to predict HLA-A*11:01-binding peptides2019

    • Author(s)
      小松利広、清水健之、町田香織、山下慶子、中村祥紀、宇高恵子
    • Organizer
      第23回日本がん免疫学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] ゲノム編集によるTAP欠損細胞を使ったMHCクラスI分子と抗原ペプチドの結合相互作用解析法2019

    • Author(s)
      清水健之、小松利広、深澤太郎、片岡佐誉、宇高恵子
    • Organizer
      第23回日本がん免疫学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] Augmentation of CTL-mediated anti-tumor responses by cross-presentation of a tumor antigen OVA by endothelial cells2019

    • Author(s)
      笠井道之、青井二郎、山本快亮、木嶋美香、小松利広、岩出良介、森田志保、山上卓士、坂口奈央樹、辛島 尚、井上啓史、宇高恵子
    • Organizer
      第23回日本がん免疫学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] WT抗原を標的とした前立腺癌に対するペプチドワクチン療法の臨床試験(第20報)2019

    • Author(s)
      北島清彰、北島彰子、竹内 保、降幡睦夫、宇高恵子
    • Organizer
      第23回日本がん免疫学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] A phase I clinical study of WT1 immunotherapy against bone and soft-tissue malignancies2019

    • Author(s)
      Hirofumi Namba, Motohiro Kawasaki, Tatsuo Iiyama Masahiko Ikeuchi, Mistuhiko Miyamura, Shun Doi, Keiko Udaka
    • Organizer
      第23回日本がん免疫学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] A phase I clinical study of WT1 immunotherapy against myelodysplastic syndrome2019

    • Author(s)
      Taniguchi A, Takeuchi A, IkezoeT T, Kojima K, Yokoyama A, Miyamura M, Doi S, Udaka K
    • Organizer
      第23回日本がん免疫学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] 初発悪性神経膠腫に対するWT1-W10免疫療法2019

    • Author(s)
      川西 裕、宇高恵子、土肥 俊、八幡俊男、中居永一、福田 仁、福井直樹、上羽哲也
    • Organizer
      第23回日本がん免疫学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] CTL lines specific for a wild type tumor antigen exert tumor regulatory activity in vivo2019

    • Author(s)
      Kasai M, Komatsu T, Sakaguti N, Kishi H, Udaka K
    • Organizer
      第23回日本がん免疫学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] ペプチターゼ耐性ペプチドを用いたMHC class II結合性ペプチドの特異性解析と自動予測2019

    • Author(s)
      宇高恵子
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Research-status Report
  • [Presentation] CTL lines specific for a wild type tumor antigen exert tumor regulatory activity in vivo. A combination immunotherapy with an androgen antagonist and peptide induces effective anti-tumor responses2019

    • Author(s)
      Kasai M, Komatsu T, Sakaguti N, Kishi H, Udaka K
    • Organizer
      第48回日本免疫学会
    • Related Report
      2019 Research-status Report
  • [Presentation] Construction of a computational platform to predict HLA-A*11:01 binding peptides2019

    • Author(s)
      Udaka K, Komatsu T, Shimizu T
    • Organizer
      第48回日本免疫学会
    • Related Report
      2019 Research-status Report
  • [Book] イヤーノート 20232022

    • Author(s)
      岡庭 豊(編集)
    • Total Pages
      3664
    • Publisher
      メディック メディア
    • ISBN
      9784896328530
    • Related Report
      2021 Annual Research Report
  • [Book] Year Note 2021 内科・外科編(分担執筆)2021

    • Author(s)
      宇高恵子
    • Total Pages
      20
    • Publisher
      メディックメディア
    • ISBN
      9784896327977
    • Related Report
      2020 Research-status Report
  • [Remarks] Department of Immunology

    • URL

      http://www.kochi-u.ac.jp/kms/ff_immnl/index.htm

    • Related Report
      2020 Research-status Report

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Published: 2019-04-18   Modified: 2024-12-25  

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