2020 Fiscal Year Final Research Report
Molecular mechanism underlying the metabolic reprogramming of tumor microenvironment by the combination therapy of metformin and anti-PD-1 antibody
| Project/Area Number |
19K23887
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| Research Category |
Grant-in-Aid for Research Activity Start-up
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| Allocation Type | Multi-year Fund |
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| Review Section |
0901:Oncology and related fields
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| Research Institution | Okayama University |
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Principal Investigator |
Nishida Mikako 岡山大学, 医歯薬学総合研究科, 助教 (60844644)
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| Project Period (FY) |
2019-08-30 – 2021-03-31
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| Keywords | メトホルミン / 腫瘍微小環境 / 代謝 / 活性酸素 / IFNγ / CD8 TILs |
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| Outline of Final Research Achievements |
In the combination therapy model with metformin and anti-PD-1 Ab, we tried to identify the intrinsic factor(s) of tumor infiltrating CD8+ T lymphocytes (CD8TILs) , which was involved in the metabolic reprogramming of the tumor microenvironment. To this end, we performed FACS analysis of both CD8TILs and tumor cells simultaneously. We found that metformin-induced mitochondrial ROS (mtROS) elevates Glut-1 on the cell surfaced and Nrf2/mTORC1 in CD8TILs, which induced glycolysis elevation and cell proliferation, respectively. Intriguingly, the robust production of IFNγ by the combination therapy, not by the monotherapy, was found involved in downregulation of the glycolysis and the oxidative phosphorylation (OxPhos) of tumor cells. Thus, we could successfully identify the molecular mechanism of the combination therapy-induced metabolic reprogramming of the tumor microenvironment.
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| Free Research Field |
腫瘍免疫
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| Academic Significance and Societal Importance of the Research Achievements |
近年、がん治療に免疫チェックポイント阻害剤が用いられており、治療効果が従来の治療法と比較して有効であるとされた。しかしその一方で効果が限定的、副作用の問題など解決すべき課題が残されている。我々はこれまでに2 型糖尿病治療薬のメトホルミンと抗PD-1抗体を併用することで相乗的な抗腫瘍効果を示すことを見出したが、詳細な分子メカニズムについては不明な点が多い。この機序解明は今後の免疫療法の発展にも重要である。本研究課題はメトホルミンが誘導する抗腫瘍効果の分子メカニズムの詳細部分を明らかにしたものであり、今後の免疫療法の発展のために重要な基礎的知見を提供することから、社会的な貢献は大きいと考えられる。
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