Low-Dose Metformin Reprograms the Tumor Immune Microenvironment in Human Esophageal Cancer: Results of a Phase II Clinical Trial
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 anticancer immunity in esophageal squamous cell carcinoma (ESCC). Experimental Design: We analyzed matched pre- and posttreatment 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 toward “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 the ESCC mouse model, short-term metformin treatment reprogrammed the TIME in a similar fashion to humans, whereas long-term treatment further shifted the TIME toward an active state (e.g., reduction in CD4+ FoxP3+ regulatory T…
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