| Project/Area Number |
17K11276
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Obstetrics and gynecology
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| Research Institution | Nara Medical University (2019)
Osaka University (2017-2018) |
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Principal Investigator |
Mabuchi Seiji 奈良県立医科大学, 医学部, 講師 (00452441)
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| Co-Investigator(Kenkyū-buntansha) |
澤田 健二郎 大阪大学, 医学系研究科, 講師 (00452392)
橋本 香映 大阪大学, 医学系研究科, 助教 (90612078)
松本 有里 大阪大学, 医学部附属病院, 助教 (90756488)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 卵巣癌 / MDSC / 癌幹細胞 / 免疫逃避 / PD-L1 / PGE2 / 治療抵抗性 / 抗腫瘍免疫 / 免疫寛容 / 免疫療法 / 耐性機構 |
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| Outline of Final Research Achievements |
In the current study, we have found that MDSC and CSC (ALDH-high cells) were more frequently observed in G-CSF-expressing cell-derived tumors than in Mock-expressing cell-derived tumors. Co-culture experiments revealed that MDSC increased the number of CSC via the production of PGE2. Moreover, PGE2 produced by MDSC increased tumor PD-L1 expression via the mammalian target of rapamycin (mTOR) pathway in ovarian cancer cells. In an in vitro experiment in which ovarian cancer cells were co-cultured with MDSC, higher expression of PD-L1 was observed in CSC than in non-CSC (ALDH-low cells). Furthermore, by immunofluorescence staining, we found that PD-L1 was co-expressed with ALDH1 in in vivo mouse models. In conclusion, PGE2 produced by MDSC increases the stem cell-like properties and tumor PD-L1 expression in epithelial ovarian cancer. Depleting MDSC may be therapeutically effective against ovarian cancer by reducing the number of CSC and tumor PD-L1 expression.
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| Academic Significance and Societal Importance of the Research Achievements |
MDSCが増加した卵巣癌(G-CSF産生またはIL-6産生腫瘍) は標準治療に抵抗性を示すため、予後は極めて不良である。我々は、MDSCがPGE2の産生を介して癌幹細胞化と免疫寛容の両方を誘導し、卵巣癌の進展を促進することを見いだした。これらの成果は、本病態の治療抵抗性の原因解明に寄与するだけでなく、MDSCやPGE2を阻害する治療が、癌幹細胞化と免疫逃避機構の両方を抑制し、本病態に対する新規個別化治療になり得ることを示す。我々の研究によると、MDSCが増加した卵巣癌や約10%の頻度で存在する。難治性卵巣癌患者の予後改善に寄与する研究成果であり、その医学的意義は大きい。
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