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Immune response-associated gene expression profiling for biomarker development in hypermutated tumors

Research Project

Project/Area Number 17K07209
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Tumor diagnostics
Research InstitutionShizuoka Cancer Center Research Institute

Principal Investigator

Akiyama Yasuto  静岡県立静岡がんセンター(研究所), その他部局等, 研究員 (70222552)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
KeywordsHypermutator / 腫瘍内浸潤リンパ球 / T細胞受容体 / 次世代シークエンサー / がん免疫療法 / 高頻度遺伝子変異腫瘍 / がんエキソーム解析 / 免疫応答関連遺伝子 / 免疫チェックポイント抗体 / がんエクソーム解析 / 免疫学 / 癌 / ゲノム / マイクロアレイ
Outline of Final Research Achievements

Hypermutator tumors from 108 cancer patients with more than 500 SNV (20 TMB) were analyzed in terms of immune response-associated gene expression with aiming at the identification of biomarkers associated prognosis. In hypermutator tumors, specific T-cell activating genes, such as PD-L1, TNFSF9, IL-6, GZMB and CD3G, were upregulated in expression, which may suggest the functional activation of intratumoral T-cells. Hypermutator tumors with immune-inflamed signature (PD-L1+CD8+) showed a better prognosis compared with other immune types. Therefore, not only a hepermutation, but also the initiation of TIL induction against tumor-specific neoantigens in the tumor can be needed to obtaion a better cancer prognosis.

Academic Significance and Societal Importance of the Research Achievements

Hypermutator腫瘍は、PD-L1やTILマーカーと並んで免疫チェックポイント抗体治療の良好な予後を示唆するマーカーとして認知されている。しかし、これまでに多くの癌腫の患者において免疫チェックポイント抗体を用いた臨床試験が実施されてきているが、hypermutator腫瘍でも治療予後の悪い症例が少なからず存在する。治療前のhypermutator腫瘍内での免疫応答に関連する遺伝子の発現解析を行い、予後と相関するバイオマーカーを同定すればさらに治療予後の良い症例を選別することが可能となり、引いては抗体医療のコストパフォーマンスの改善にもつながると考えられる。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (21 results)

All 2020 2019 2018 2017

All Journal Article (18 results) (of which Peer Reviewed: 18 results,  Open Access: 11 results) Presentation (3 results)

  • [Journal Article] Japanese version of The Cancer Genome Atlas, JCGA, established using fresh frozen tumors obtained from 5143 cancer patients.2020

    • Author(s)
      Nagashima T, Yamaguchi K, Terashima M, et al.
    • Journal Title

      Cancer Science

      Volume: 111 Issue: 2 Pages: 687-699

    • DOI

      10.1111/cas.14290

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Assessment of associations between clinical and immune microenvironmental factors and tumor mutation burden in resected nonsmall cell lung cancer by applying machine learning to whole-slide images.2020

    • Author(s)
      Ono A, Terada Y, Kawata T, Serizawa M, Isaka M, Kawabata T, Imai T, Mori K, Muramatsu K, Hayashi I, Kenmotsu H, Ohshima K, Urakami K, Nagashima T, Kusuhara M, Akiyama Y, Sugino T, Ohde Y, Yamaguchi K, Takahashi T.
    • Journal Title

      Cancer Med.

      Volume: - Issue: 13 Pages: 4864-4875

    • DOI

      10.1002/cam4.3107

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Antitumor activity of the PD-1/PD-L1 binding inhibitor BMS-202 in the humanized MHC-double knockout NOG mouse2019

    • Author(s)
      Ashizawa T, Iizuka A, Tanaka E, Kondou R, Miyata H, Maeda C, Sugino T, Yamaguchi K, Ando T, Ishikawa Y, Ito M, Akiyama Y.
    • Journal Title

      Biomedical Research

      Volume: 40 Issue: 6 Pages: 243-250

    • DOI

      10.2220/biomedres.40.243

    • NAID

      130007761178

    • ISSN
      0388-6107, 1880-313X
    • Year and Date
      2019-12-01
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of a neoantigen epitope in a melanoma patient with good response to anti-PD-1 antibody therapy2019

    • Author(s)
      Nonomura C, Otsuka M, Kondou R, Iizuka A, Miyata H, Ashizawa T, Sakura N, Yoshikawa S, Kiyohara Y, Ohshima K, Urakami K, Nagashima T, Ohnami S, Kusuhara M, Mitsuya K, Hayashi N, Nakasu Y, Mochizuki T, Yamaguchi K, Akiyama Y
    • Journal Title

      Immunol Lett

      Volume: 208 Pages: 52-59

    • DOI

      10.1016/j.imlet.2019.02.004

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A T-cell-engaging B7-H4/CD3-bispecific Fab-scFv Antibody Targets Human Breast Cancer2019

    • Author(s)
      Iizuka Akira、Nonomura Chizu、Ashizawa Tadashi、Kondou Ryota、Ohshima Keiichi、Sugino Takashi、Mitsuya Koichi、Hayashi Nakamasa、Nakasu Yoko、Maruyama Kouji、Yamaguchi Ken、Akiyama Yasuto
    • Journal Title

      Clinical Cancer Research

      Volume: 25 Issue: 9 Pages: 2925-2934

    • DOI

      10.1158/1078-0432.ccr-17-3123

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mutational burden and signatures in 4000 Japanese cancers provide insights into tumorigenesis and response to therapy2019

    • Author(s)
      Hatakeyama K, Akiyama Y
    • Journal Title

      Cancer Sci

      Volume: 110 Issue: 8 Pages: 2620-2628

    • DOI

      10.1111/cas.14087

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Imaging analysis of EGFR mutated cancer cells using peptide nucleic acid (PNA)?DNA probes2019

    • Author(s)
      Shigeto Hajime、Ohtsuki Takashi、Iizuka Akira、Akiyama Yasuto、Yamamura Shohei
    • Journal Title

      The Analyst

      Volume: 144 Issue: 15 Pages: 4613-4621

    • DOI

      10.1039/c9an00725c

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Driver gene alterations and activated signaling pathways toward malignant progression of gastrointestinal stromal tumors.2019

    • Author(s)
      Ohshima K, Fujiya K, Nagashima T, Ohnami S, Hatakeyama K, Urakami K, Naruoka A, Watanabe Y, Moromizato S, Shimoda Y, Ohnami S, Serizawa M, Akiyama Y, Kusuhara M, Mochizuki T, Sugino T, Shiomi A, Tsubosa Y, Uesaka K, Terashima M, Yamaguchi K.
    • Journal Title

      Cancer Science

      Volume: 110 Issue: 12 Pages: 3821-3833

    • DOI

      10.1111/cas.14202

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Impact of combination therapy with anti-PD-1 blockade and a STAT3 inhibitor on the tumor-infiltrating lymphocyte status.2019

    • Author(s)
      Ashizawa T, Iizuka A, Maeda C, Tanaka E, Kondou R, Miyata H, Sugino T, Kawata T, Deguchi S, Mitsuya K, Hayashi N, Asai A, Ito M, Yamaguchi K, Akiyama Y.
    • Journal Title

      Immunol Lett.

      Volume: 216 Pages: 43-50

    • DOI

      10.1016/j.imlet.2019.10.003

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Classification of tumor microenvironment immune types based on immune response-associated gene expression2019

    • Author(s)
      Kondou R, Iizuka A, Nonomura C, Miyata H, Ashizawa T, Nagashima T, Ohshima K, Urakami K, Kusuhara M, Yamaguchi K, Akiyama Y
    • Journal Title

      Int J Oncol

      Volume: 54 Pages: 219-228

    • DOI

      10.3892/ijo.2018.4617

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] <b>Tumor mutational burden analysis of 2,000 Japanese cancer genomes using whole exome and targeted gene panel </b><b>sequencing </b>2018

    • Author(s)
      Hatakeyama K, Nagashima T, Urakami K, Ohshima K, Serizawa M, Ohnami S, Shimoda Y, Ohnami S, Maruyama K, Naruoka A, Akiyama Y, Kusuhara M, Mochizuki T, Yamaguchi K
    • Journal Title

      Biomedical Research

      Volume: 39 Issue: 3 Pages: 159-167

    • DOI

      10.2220/biomedres.39.159

    • NAID

      130007396436

    • ISSN
      0388-6107, 1880-313X
    • Year and Date
      2018-06-01
    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Molecular profiling and sequential somatic mutation shift in hypermutator tumours harbouring POLE mutations2018

    • Author(s)
      Hatakeyama K, Ohshima K, Nagashima T, Ohnami S, Ohnami S, Serizawa M, Shimoda Y, Maruyama K, Akiyama Y, Urakami K, Kusuhara M, Mochizuki T, Yamaguchi K
    • Journal Title

      Sci Rep

      Volume: 8 Issue: 1 Pages: 8700-8700

    • DOI

      10.1038/s41598-018-26967-4

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Changes in programmed death ligand 1 expression in non-small cell lung cancer patients who received anticancer treatments2018

    • Author(s)
      Omori S, Kenmotsu H, Abe M, Watanabe R, Sugino T, Kobayashi H, Nakashima K, Wakuda K, Ono A, TairaT, Naito T, Murakami H, Ohde Y, Endo M, Akiyama Y, Nakajima T, Takahashi T
    • Journal Title

      Int J Clin Oncol

      Volume: 23 Issue: 6 Pages: 1052-1059

    • DOI

      10.1007/s10147-018-1305-4

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Integrated analysis of gene expression and copy number identified potential cancer driver genes with amplification-dependent overexpression in 1,454 solid tumors.2017

    • Author(s)
      Ohshima K, Hatakeyama K, Nagashima T, Watanabe Y, Kanto K, Doi Y, Ide T, Shimoda Y, Tanabe T, Ohnami S, Ohnami S, Serizawa M, Maruyama K, Akiyama Y, Urakami K, Kusuhara M, Mochizuki T, Yamaguchi K
    • Journal Title

      Scientific Reports

      Volume: 7 Issue: 1 Pages: 641-641

    • DOI

      10.1038/s41598-017-00219-3

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The anti-tumor activity of the STAT3 inhibitor STX-0119 occurs via promotion of tumor-infiltrating lymphocyte accumulation in temozolomide-resistant glioblastoma cell line2017

    • Author(s)
      Akiyama Yasuto、Nonomura Chizu、Ashizawa Tadashi、Iizuka Akira、Kondou Ryota、Miyata Haruo、Sugino Takashi、Mitsuya Koichi、Hayashi Nakamasa、Nakasu Yoko、Asai Akira、Ito Mamoru、Kiyohara Yoshio、Yamaguchi Ken
    • Journal Title

      Immunology Letters

      Volume: 190 Pages: 20-25

    • DOI

      10.1016/j.imlet.2017.07.005

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Sutureless microvascular anastomosis assisted by an expandable shape-memory alloy stent2017

    • Author(s)
      Saegusa Noriko、Sarukawa Shunji、Ohta Kunihiro、Takamatsu Kensuke、Watanabe Mitsuhiro、Sugino Takashi、Nakagawa Masahiro、Akiyama Yasuto、Kusuhara Masatoshi、Kishi Kazuo、Inoue Keita
    • Journal Title

      PLOS ONE

      Volume: 12 Issue: 7 Pages: e0181520-e0181520

    • DOI

      10.1371/journal.pone.0181520

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] In situ delivery and production system of trastuzumab scFv with Bifidobacterium2017

    • Author(s)
      Kikuchi Takeshi、Shimizu Hitomi、Akiyama Yasuto、Taniguchi Shun'ichiro
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 493 Issue: 1 Pages: 306-312

    • DOI

      10.1016/j.bbrc.2017.09.026

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Immune response-associated gene profiling in Japanese melanoma patients using multi-omics analysis2017

    • Author(s)
      Akiyama Yasuto、Kiyohara Yoshio、Yoshikawa Shusuke、Otsuka Masaki、Kondou Ryota、Nonomura Chizu、Miyata Haruo、Iizuka Akira、Ashizawa Tadashi、Ohshima Keiichi、Urakami Kenichi、Nagashima Takeshi、Kusuhara Masatoshi、Sugino Takashi、Yamaguchi Ken
    • Journal Title

      Oncology Reports

      Volume: 39 Pages: 1125-1131

    • DOI

      10.3892/or.2017.6173

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 抗PD-1抗体療法が奏功したメラノーマ症例におけるネオアンチゲンの同定2019

    • Author(s)
      秋山靖人
    • Organizer
      第78回癌学会学術総会(京都)
    • Related Report
      2019 Annual Research Report
  • [Presentation] Characterization of hypermutated tumors based on tumor microenvironment immune types classification2018

    • Author(s)
      Akiyama Y, Iizuka A, Nagashima T, Shimoda Y, Tanabe T, Ohnami S, Ohnami S, Ohshima K, Urakami K, Kusuhara M, Mochizuki T, Yamaguchi K
    • Organizer
      第77回日本癌学会総会
    • Related Report
      2018 Research-status Report
  • [Presentation] Classification of tumor microenvironment immune types based on the immune response-associated gene expression2017

    • Author(s)
      Akiyama Y, Iizuka A, Nagashima T, Shimoda Y, Tanabe T, Ohnami S, Ohnami S, Ohshima K, Urakami K, Kusuhara M, Mochizuki T, Yamaguchi K
    • Organizer
      第76回日本癌学会総会
    • Related Report
      2017 Research-status Report

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Published: 2017-04-28   Modified: 2021-02-19  

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