| Project/Area Number |
18K14893
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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 47030:Pharmaceutical hygiene and biochemistry-related
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| Research Institution | Hokkaido University |
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Principal Investigator |
Kitai Yuichi 北海道大学, 薬学研究院, 助教 (90756165)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | 自然免疫 / がん免疫 / DAMPs / 細胞死 / 抗がん剤 / プログラム細胞死 |
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| Outline of Final Research Achievements |
Damage-associated molecular patterns (DAMPs) contribute to antitumor immunity during cancer chemotherapy. We previously demonstrated that topotecan (TPT), a topoisomerase I inhibitor, induces DAMP secretion from cancer cells, which activates STING-mediated antitumor immune responses. However, how TPT induces DAMP secretion in cancer cells is yet to be elucidated. Here, we identified RPLX, a 60S ribosomal protein, as a novel TPT target and showed that TPT inhibited pre-ribosomal subunit formation via its binding to RPLX, resulting in the induction of DAMP-mediated antitumor immune activation independent of TOP1. RPLX knockdown induced DAMP secretion and increased the CTL population but decreased the Treg population in a B16-F10 murine melanoma model, which sensitized B16-F10 tumors against PD-1 blockade. Our study identified a novel TPT target protein and showed that ribosomal stress is a trigger of DAMP secretion, which contributes to antitumor immunotherapy.
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| Academic Significance and Societal Importance of the Research Achievements |
先行研究より、抗がん剤であるトポテカンは既知の標的であるトポイソメラーゼI以外にも未知の標的が存在することが示唆されていたが、その詳細は不明であった。本研究ではトポテカンの新規標的タンパクを明らかにし、このタンパクを阻害することでがん免疫療法の改良につながることを解明した。今後はこの新規標的タンパクを特異的に阻害する化合物の作成とその評価に取り組むことで、既存のがん免疫療法の治療効果を改善することに挑戦していきたい。
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