Low-dose metformin reprograms the tumor immune microenvironment in human esophageal cancer: Results of a phase II clinical trial

Shuhong Wang, Yusheng Lin, Xiao Xiong, Lu Wang, Yi Guo, Yuping Chen, Shaobin Chen, Geng Wang, Peng Lin, Hongcai Chen, Sai-Ching J Yeung, Edwin Bremer, Hao Zhang*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

PURPOSE: The tumor immune microenvironment (TIME) has an important impact on response to cancer immunotherapy using immune checkpoint inhibitors. Specifically, an "infiltrated-excluded"/"cold" TIME is predictive of poor response. The antidiabetic agent metformin may influence anti-cancer immunity in esophageal squamous cell carcinoma (ESCC).

EXPERIMENTAL DESIGN: We analyzed matched pre- and post-treatment ESCC specimens in a phase II clinical trial of low-dose metformin treatment (250 mg/day) to evaluate direct anti-ESCC activity and TIME-reprogramming. Follow-up correlative studies using a carcinogen-induced ESCC mouse model were performed with short-term (1 week) or long-term (12 weeks) low-dose metformin (50 mg/kg/day) treatment.

RESULTS: In the clinical trial, low-dose metformin did not affect proliferation or apoptosis in ESCC tumors as assayed by Ki67 and cleaved caspase-3 immunostaining. However, metformin reprogrammed the TIME towards "infiltrated-inflamed" and increased the numbers of infiltrated CD8+ cytotoxic T-lymphocyte and CD20+ B-lymphocyte. Further, an increase in tumor-suppressive (CD11c+) and a decrease in tumor-promoting (CD163+) macrophages were observed. Metformin augmented macrophage-mediated phagocytosis of ESCC cells in vitro. In ESCC mouse model, short-term metformin treatment reprogrammed the TIME in a similar fashion to humans, whereas long-term treatment further shifted the TIME towards an active state (e.g., reduction in CD4+ FoxP3+ Tregs) and inhibited ESCC growth. In both humans and mice, metformin triggered AMPK activation and STAT3 inactivation, and altered the production of effector cytokines (i.e. TNF-α, IFN-γ, IL-10) in the immune cells.

CONCLUSIONS: Low-dose metformin reprograms the TIME to an activated status and may be a suitable immune response modifier for further investigation in ESCC patients.

Original languageEnglish
Pages (from-to)4921-4932
Number of pages12
JournalClinical Cancer Research
Volume26
Issue number18
Early online date4-Aug-2020
DOIs
Publication statusPublished - 15-Sep-2020

Cite this