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Enhancement of anti-tumor immunity by post-translational modification of MICA

Research Project

Project/Area Number 17K09405
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Gastroenterology
Research InstitutionThe University of Tokyo

Principal Investigator

Sato Masaya  東京大学, 医学部附属病院, 助教 (30722665)

Co-Investigator(Kenkyū-buntansha) 大塚 基之  東京大学, 医学部附属病院, 講師 (90518945)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords腫瘍免疫 / MICA / 免疫療法 / 切断酵素 / 分泌 / 癌 / 免疫学
Outline of Final Research Achievements

A single nucleotide polymorphism at the upstream of MICA gene is associated with the susceptibility of hepatocellualr carcinogenesis. The SNP is associated with the MICA transcriptional levels, which are linked with the activity of anti-tumor immunity. However, the regulation of MICA on the cancer cell surface is not only dependent on the transcriptin but on the post-trasnlational modification, that is, the clevage of MICA from the cell surface into the supernatant. In this study, from the library scree, FAAH inhibitor was identified as an inhibitor of MICA clevage. FAAH inhibitor enhanced TIMP3 expression, which in turn inhibited the MICA shedding. FAAH inhibitor may be useful for the enhancement of anti-tumor immunity through MICA expression on the cancer cell surface.

Academic Significance and Societal Importance of the Research Achievements

本研究によって、肝癌発癌に関与する遺伝子であることが以前に同定されている自然免疫関連分子であるMICAの癌細胞表面からの切断分泌を阻害する化合物を同定できた。
MICA蛋白は癌細胞表面に表出されると "eat-me signal"として作用し、免疫応答を惹起するトリガーとなるが、癌細胞ではMICA蛋白を切断して上清に分泌させてしまう機能がある。本研究によってFAAH阻害剤がMICA蛋白の切断を阻害し、癌細胞表面に表出されたMICA蛋白の量を維持する機能があることが判明した。この知見を応用すれば、癌免疫を増強し、発がん抑制や癌治療の増強につながることが期待される。

Report

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

    (7 results)

All 2019 2018 2017

All Journal Article (7 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 7 results,  Open Access: 7 results,  Acknowledgement Compliant: 1 results)

  • [Journal Article] Machine-learning Approach for the Development of a Novel Predictive Model for the Diagnosis of Hepatocellular Carcinoma2019

    • Author(s)
      Sato Masaya、Morimoto Kentaro、Kajihara Shigeki、Tateishi Ryosuke、Shiina Shuichiro、Koike Kazuhiko、Yatomi Yutaka
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 7704-7704

    • DOI

      10.1038/s41598-019-44022-8

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Impact of direct-acting antivirals on early recurrence of HCV-related HCC: Comparison with interferon-based therapy2019

    • Author(s)
      Nishibatake Kinoshita Mizuki、Minami Tatsuya、Tateishi Ryosuke、Wake Taijiro、Nakagomi Ryo、Fujiwara Naoto、Sato Masaya、Uchino Koji、Enooku Kenichiro、Nakagawa Hayato、Asaoka Yoshinari、Shiina Shuichiro、Koike Kazuhiko
    • Journal Title

      Journal of Hepatology

      Volume: 70 Issue: 1 Pages: 78

    • DOI

      10.1016/j.jhep.2018.09.029

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inhibition of HBV Transcription From cccDNA With Nitazoxanide by Targeting the HBx?DDB1 Interaction2019

    • Author(s)
      Sekiba Kazuma、Otsuka Motoyuki、Ohno Motoko、Yamagami Mari、Kishikawa Takahiro、Suzuki Tatsunori、Ishibashi Rei、Seimiya Takahiro、Tanaka Eri、Koike Kazuhiko
    • Journal Title

      Cellular and Molecular Gastroenterology and Hepatology

      Volume: 7 Issue: 2 Pages: 297-312

    • DOI

      10.1016/j.jcmgh.2018.10.010

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inflammation and de-differentiation in pancreatic carcinogenesis2018

    • Author(s)
      Seimiya Takahiro、Otsuka Motoyuki、Iwata Takuma、Tanaka Eri、Suzuki Tatsunori、Sekiba Kazuma、Yamagami Mari、Ishibashi Rei、Koike Kazuhiko
    • Journal Title

      World Journal of Clinical Cases

      Volume: 6 Issue: 15 Pages: 882-891

    • DOI

      10.12998/wjcc.v6.i15.882

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] ISGF3 with reduced phosphorylation is associated with constitutive expression of interferon-induced genes in aging cells2018

    • Author(s)
      Yamagami Mari、Otsuka Motoyuki、Kishikawa Takahiro、Sekiba Kazuma、Seimiya Takahiro、Tanaka Eri、Suzuki Tatsunori、Ishibashi Rei、Ohno Motoko、Koike Kazuhiko
    • Journal Title

      npj Aging and Mechanisms of Disease

      Volume: 4 Issue: 1 Pages: 11-11

    • DOI

      10.1038/s41514-018-0030-6

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Transcriptional activation of the MICA gene with an engineered CRISPR-Cas9 system2017

    • Author(s)
      Sekiba K, Yamagami M, Otsuka M, Suzuki T, Kishikawa T, Ishibashi R, Ohno M, Sato M, Koike K
    • Journal Title

      Biochem Biophys Res Commun

      Volume: - Issue: 2 Pages: 521-525

    • DOI

      10.1016/j.bbrc.2017.03.076

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Mortality and hemorrhagic complications associated with radiofrequency ablation for treatment of hepatocellular carcinoma in patients on hemodialysis for end-stage renal disease: A nationwide survey.2017

    • Author(s)
      Sato M, Tateishi R, Yasunaga H, Matsui H, Horiguchi H, Fushimi K, Koike K.
    • Journal Title

      J Gastroenterol Hepatol.

      Volume: 32 Issue: 11 Pages: 1873-1878

    • DOI

      10.1111/jgh.13780

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access

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

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