| Project/Area Number |
18K15076
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 49020:Human pathology-related
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| Research Institution | Tohoku University |
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Principal Investigator |
Saito Ryoko 東北大学, 大学病院, 講師 (30733349)
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| Project Period (FY) |
2018-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | EGFR-TKI / 腫瘍内免疫微小環境 / miR-1 / 治療効果予測因子 / 免疫療法 / Mef2C / miRNA / 免疫チェックポイント / EGFR-TKI耐性 / 免疫微小環境 |
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| Outline of Final Research Achievements |
The status of the tumor immune microenvironment (TIME), including lymphocyte infiltration, has been well known to provide predictive markers for the efficacy of immunotherapy. We evaluated the correlation between epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance and TIME, before and after acquiring EGFR-TKI resistance, in lung adenocarcinoma, and further explored this by in vitro studies.
As a result, infiltration levels of T cells were significantly decreased after development of EGFR-TKI resistance, and it was revealed that miR-1 was increased through myocyte enhancer factor 2C (Mef2C) upregulation, and miR-1 significantly inhibited cytokines causing inhibition of monocyte migration.
These results indicate that the Mef2C-miR-1 pathway changed the TIME, following development of EGFR-TKI resistance, and miR-1 could be a clinically useful marker to predict therapeutic efficacy of immunotherapy in lung adenocarcinoma patients with EGFR-TKI resistance.
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| Academic Significance and Societal Importance of the Research Achievements |
EGFR-TKI耐性獲得後にmiR-1が上昇している症例ではICIの治療効果は乏しいものの臨床予後は良好である可能性が高く、化学療法を含めたICI以外の治療を積極的に進めるマーカーとなり得ると考えられた。今回の結果を踏まえ、今後ヒト血清・ヒト組織におけるmiR-1発現の変化が有用となれば、現行の病理組織に基づく治療効果予測のheterogeneityによる問題点を補填することが可能となるであろう。以上より、我々の研究成果はEGFR-TKI耐性獲得肺癌患者の治療選択および治療戦略の発展に，今後多大なる貢献を果たすと考えられる．
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