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The role of blood cell-free DNA in cancer patients in systemic inflammation

Research Project

Project/Area Number 19K16827
Research Category

Grant-in-Aid for Early-Career Scientists

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

Principal Investigator

Noguchi Takuro  北海道大学, 医学研究院, 助教 (40814554)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywords腫瘍免疫学 / 肺癌 / EGFR阻害薬 / 腫瘍免疫 / EGFR変異陽性肺癌 / cfDNA / CD24 / 自然免疫応答 / 核酸受容体 / マクロファージ / 免疫チェックポイント阻害療法
Outline of Research at the Start

一部のがん患者は、非感染状態でも発熱や倦怠感といった全身性炎症反応を呈する。これらは腫瘍熱、悪液質と呼ばれる。また、全身性炎症反応自体が、がん薬物療法の治療効果に対して負の側面を持つことが示唆されている。近年、担がん患者の末梢血中には腫瘍細胞由来DNAが浮遊してい ることが明らかとなってきた。免疫学的には DNAは免疫細胞のパターン認識受容体を介して炎症を惹起し、生体防御に関わる強力な免疫刺激性分子である。そのため、本研究では、がん患者における末梢血浮遊DNAの全身性炎症反応 への関与を解明することを目的とする。

Outline of Final Research Achievements

1)EGFR(Epidermal growth factor receptor)-mutated non-small cell lung cancer (NSCLC) cells accelerated the release of cell-free DNA upon EGFR inhibition, which activated the type I interferon signaling pathway in immune cells in a Stimulator of interferon genes(STING)-dependent manner.
2)EGFR-mutated NSCLC cells upregulated an inhibitory immune checkpoint CD24 when treated with EGFR tyrosine kinase inhibitors, in cell lines and patient samples.

Academic Significance and Societal Importance of the Research Achievements

EGFR変異陽性肺癌に対するEGFR阻害薬は高い治療効果を認めるが、時間の経過とともにほとんどが耐性を獲得することが知られており、その耐性機序の理解と克服が課題である。本研究では、免疫学的観点から、この課題への研究を進めた。その結果、EGFR阻害薬によって誘導される免疫逃避機構関連因子を同定した。今後この経路を標的とした新規治療薬の開発により、EGFR変異陽性肺癌の治療成績の向上につながる可能性がある。

Report

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

    (4 results)

All 2022 2021 2019

All Presentation (4 results) (of which Int'l Joint Research: 1 results)

  • [Presentation] EGFR-mutated lung cancer cells accelerate the release of cfDNA activating innate immune pathways upon EGFR-TKI treatment2022

    • Author(s)
      Takuro Noguchi, Akihiko Shiiya, Shin Ariga, Tomohiro Goda, Yoshihito Ohhara, Jun Taguchi, Satoshi Takeuchi, Yasushi Shimizu, Ichiro Kinoshita, Hirotoshi Akita
    • Organizer
      2022 the Japanese Society of Medical Oncology Annual Meeting
    • Related Report
      2021 Annual Research Report
  • [Presentation] CD24, an immunosuppressive immune checkpoint, is up-regulated in EGFR-mutated non-small lung cancer cell lines upon EGFR-TKI treatment.2021

    • Author(s)
      Takuro Noguchi, Akihiko Shiiya, Shin Ariga, Yoshihito Ohhara, Yasushi Shimizu, Ichiro Kinoshita, Hirotoshi Akita
    • Organizer
      The 39th Sapporo International Cancer Symposium
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Cell-free DNA from EGFR-mutated lung cancer cells treated with EGFR-TKIs engages in innate immune signaling pathways2021

    • Author(s)
      Akihiko Shiiya, Takuro Noguchi, Shin Ariga, Yoshihito Ohhara, Yasushi Shimizu, Ichiro Kinoshita, Hirotoshi Akita
    • Organizer
      The 80th Annual Meeting of the Japanese Cancer Association
    • Related Report
      2021 Annual Research Report
  • [Presentation] A single institute analysis of cell-free DNA concentrations in plasma of patients with various cancer types.2019

    • Author(s)
      Noguchi T, Miyagawa M, Sekiguchi N, Gomi D, Fukushima T, Ozawa T, Kobayashi T, Taniguchi S, Koizumi T.
    • Organizer
      The 17th Annual Meeting of JSMO
    • Related Report
      2019 Research-status Report

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Published: 2019-04-18   Modified: 2023-01-30  

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