Metformin synergizes with PD-1 blockade to promote normalization of tumor vessels via CD8T cells and IFNγ

• 成果类型: Article
• 署名作者: Tokumasu, Miho; Nishida, Mikako; Zhao, Weiyang; Chao, Ruoyu; Imano, Natsumi; Yamashita, Nahoko; Hida, Kyoko; Naito, Hisamichi; Udono, Heiichiro
• 署名单位: Okayama University; Hokkaido University; Hokkaido University; Kanazawa University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13244
• DOI: 10.1073/pnas.2404778121
• 发表日期: 2024-07-23
• 关键词: endothelial-cells; t-cells; microenvironment; cancer; angiogenesis; glioblastoma; macrophages; survival; glycolysis; expression

摘要

Tumor blood vessels are highly leaky in structure and have poor blood perfusion, which hampers infiltration and function of CD8T cells within tumor. Normalizing tumor vessels is thus thought to be important in promoting the flux of immune T cells and enhancing ant- tumor immunity. However, how tumor vasculature is normalized is poorly understood. Metformin (Met) combined with ant- PD- 1 therapy is known to stimulate proliferation of and to produce large amounts of IFN gamma from tumor- infiltrating CD8T lymphocytes (CD8TILs). We found that the combination therapy promotes the pericyte coverage of tumor vascular endothelial cells (ECs) to improve blood perfusion and that it suppresses the hyperpermeability through the increase of VE- cadherin. Peripheral node addressin(PNAd) and vascular cell adhesion molecule (VCAM)- 1, both implicated to promote tumor infiltration of CD8T cells, were also increased. Importantly, tumor vessel normalization, characterized as the reduced 70- kDa dextran leakage and the enhancement of VE- cadherin and VCAM- 1, were canceled by anti- CD8 Ab or anti- IFN gamma Ab injection to mice. The increased CD8TILs were also abrogated by anti- IFN gamma Ab injection. In vascular ECs, flow cytometry analysis revealed that pSTAT1 expression was found to be associated with VE- cadherin expression. Moreover, in vitro treatment with Met and IFN gamma enhanced VE- cadherin and VCAM- 1 on human umbilical vein endothelial cells (HUVECs). The Kaplan-Meier method revealed a correlation of VE- cadherin or VCAM- 1 levels with overall survival in patients treated with immune checkpoint inhibitors. These data indicate that IFN gamma- mediated cross talk of CD8TILs with tumor vessels is important for creating a better tumor microenvironment and maintaining sustained antitumor immunity.