The mechanism of immune escape by myeloid-derived suppressor cells and cancer stem cells in ovarian cancer.
| 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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Report
(4 results)
Research Products
(18 results)
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[Journal Article] Pretreatment tumor-related leukocytosis misleads positron emission tomography-computed tomography during lymph node staging in gynecological malignancies.2020
Author(s)
Mabuchi S, Komura N, Sasano T, Shimura K, Yokoi E, Kozasa K, Kuroda H, Takahashi R, Kawano M, Matsumoto Y, Kato H, Hatazawa J, and Kimura T.
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Journal Title
Nat Commun
Volume: 11
Issue: 1
Pages: 1364-1364
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] The role of myeloid-derived suppressor cells in endometrial cancer displaying systemic inflammatory response: clinical and preclinical investigations.2020
Author(s)
4.Yokoi E, Mabuchi S, Komura N, Shimura K, Kuroda H, Kozasa K, Takahashi R, Sasano T, Kawano M, Matsumoto Y, Kodama M, Hashimoto K, Sawada K, Kimura T.
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Journal Title
Oncoimmunology.
Volume: 8
Issue: 12
Pages: e1662708-e1662708
DOI
Related Report
Peer Reviewed
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