Advances of metformin and anti-PD-1 therapy: analysis of tumor microenvironment by using multiple fluorescent immunostaining

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K16864
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Okayama University
• Principal Investigator: Kudo Ikuru 岡山大学, 医歯薬学域, 助教 (40830378)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: 腫瘍血管正常化 / メトホルミンと抗PD-1抗体併用療法 / CD8TIL / IFN-γ

Outline of Final Research Achievements

We have focused on the antitumor effect of metformin and the PD-1 blockade combination therapy (Met + αPD-1). Although the effect was believed to be caused by the robust activation/proliferation of tumor-infiltrating CD8T lymphocytes (CD8TILs), there might be additional mechanism(s). In the tumor microenvironment, we found the relationship between heterogeneous GLUT1 expressions in tumor cells and localization of tumor vessels. To reveal the effect of Met + αPD-1, we investigated the normalization of tumor vessels. We detected the tumor vessel normalization by the increased pericyte coverage on endothelial cells, decreased 70-kDa dextran leakage and increased VE-cadherin expression. Those were canceled by anti-CD8 Ab (but not anti-CD4 Ab and anti-NK Ab) or anti-IFNγ Ab injection to mice. These data indicate that metformin synergizes with PD-1 inhibition to create a positive feedback loop between CD8TILs and tumor vessels via IFNγ, resulting in durable antitumor immunity.

Free Research Field

生命科学

Academic Significance and Societal Importance of the Research Achievements

がん免疫療法では、腫瘍微小環境がどのように形成されているのかと、がん細胞を攻撃するCD8T細胞の働きを明らかにする必要がある。本研究では、がん細胞とCD8T細胞のグルコースの取り合いという観点から、GLUT1の発現を中心に、腫瘍微小環境が治療の前後でどのように変化するかを時空間的に解析した。その結果、メトホルミンと抗PD-1抗体併用療法において、CD8TILががん細胞を攻撃するだけでなく、腫瘍血管の正常化にも寄与していることが明らかになった。このことから、腫瘍微小環境の特徴である低グルコース、低酸素、低pHが、腫瘍血管正常化により一挙に解決できる可能性が見出された。