Molecular mechanism underlying the metabolic reprogramming of tumor microenvironment by IFNg

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K15505
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Okayama University
• Principal Investigator: Nishida Mikako 岡山大学, 医歯薬学域, 助教 (60844644)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 腫瘍微小環境 / 代謝 / IFNγ / 腫瘍浸潤CD8T細胞 / 腫瘍免疫 / メトホルミン

Outline of Final Research Achievements

We found that combined treatment with metformin and anti-PD-1 antibodies increased the metabolism of tumor-infiltrating CD8 T cells and decreased the metabolism of tumor cells. We hypothesized that IFNγ, an important cytokine for antitumor immune responses, is involved in this metabolic modification of the tumor microenvironment. In fact, treatment of tumor cells with IFNγ significantly reduced the expression of metabolic-related molecules. We also identified molecules involved in metabolic regulation, and found that tumor cells and CD8 T cells exhibit opposite functions. Furthermore, it was found that tumor cells lacking this molecule not only have a decreased metabolism, but also lose the conventional IFNγ function and immunotherapeutic effect, and this study reveals that it is an important molecule that controls antitumor effects.

Free Research Field

腫瘍免疫

Academic Significance and Societal Importance of the Research Achievements

現在、免疫治療を阻む要因として腫瘍微小環境における腫瘍細胞と免疫細胞(主にCD8T 細胞)の代謝競合を是正することが重要とされている。そのためには腫瘍細胞の代謝を低下させ、その一方でCD8T細胞の代謝を上昇させる必要がある。それを同時に実現できる代謝介入によるがん治療法は未だ確立されていないが、本研究を通して腫瘍細胞とCD8T細胞を腫瘍退縮へ優位な方向へ代謝や機能を同時に制御する分子の同定ならびにその制御機構の一端を解明できたことは、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に繋がり、社会的な貢献は大きいと考えられる。