| Project/Area Number |
16K15666
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| Research Category |
Grant-in-Aid for Challenging Exploratory Research
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| Allocation Type | Multi-year Fund |
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| Research Field |
Orthopaedic surgery
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| Research Institution | Okayama University |
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Principal Investigator |
OZAKI toshifumi 岡山大学, 医歯薬学総合研究科, 教授 (40294459)
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| Co-Investigator(Kenkyū-buntansha) |
榮川 伸吾 岡山大学, 医歯薬学総合研究科, 助教 (40635265)
長谷井 嬢 岡山大学, 医歯薬学総合研究科, 助教 (40636213)
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| Research Collaborator |
UEHARA takenori
UDONO heiichiro
FUJIWARA tomohiro
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
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| Keywords | immunometabolism / 骨髄球由来抑制細胞 / 腫瘍浸潤マクロファージ / metformin / osteosarcoma / cancer immunotherapy / 骨髄由来免疫抑制細胞(MDSCs) / 腫瘍浸潤マクロファージ(TAMs) / tumor immunity / tumor microenvironment / 骨軟部悪性腫瘍 / 免疫療法 / メトホルミン / 代謝制御 / 骨軟部肉腫 / 免疫モニタリング |
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| Outline of Final Research Achievements |
Metformin induces CD11b+-cell-mediated growth inhibition of a K7M2neo osteosarcoma independent of T cells. PMN-MDSCs were significantly reduced in both spleens and tumors following Metformin treatment. In TAMs, production of IL-12 and TNF-α, but not IL-10, became apparent, and elevation of MHC class II with reduction of CD206 was observed, indicating a shift from an M2- to M1-like phenotype via metformin administration. Metformin treatment leads metabolic reprogramming in tumor infiltrated CD11b+ cells. Tumor infiltrated CD11b+ cells were decreased basal respiration and the OCR/ECAR ratio. In addition, uptake of fatty acids was decreased in MDSCs and TAMs, and uptake of glucose was decreased in MDSCs only. Our results suggest that metformin redirects the metabolism of CD11b+ cells to lower oxidative phosphorylation (OXPHOS) while elevating glycolysis, thereby pushing the microenvironment to a state that inhibits the osteosarcoma growth.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究では，骨肉腫マウスモデルにおいてメトホルミンの骨髄球系細胞を主体とした免疫を介した抗腫瘍効果が明らかとなった．また，メトホルミンが骨髄球系細胞の好気的解糖を低下させることでMDSCやM2-like TAMが腫瘍内で減少したことが明らかとなった．これらの結果から，メトホルミンが腫瘍に浸潤した骨髄球系細胞の代謝を制御し，腫瘍微小環境を改変することで抗腫瘍効果を発揮することが示された．
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