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Metformin Downregulates PD-L1 Expression in Esophageal Squamous Cell Catrcinoma by Inhibiting IL-6 Signaling Pathway
1Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Purpose:
To characterize the mechanism by which metformin inhibits PD-L1 expression in esophageal squamous cell carcinoma (ESCC) and to evaluate the effect of metformin on the antitumor immune response.
Methods:
The Cancer Genome Atlas (TCGA) database was used to analyze the correlations between IL-6 and prognosis and between IL-6 and PD-L1 gene expression in esophageal cancer. Reverse transcription-quantitative polymerase chain reaction (RT-PCR), Western blotting and immunofluorescence were used to study the mechanism by which metformin affects PD-L1 expression. Additionally, T cell function was assessed in a coculture system containing ESCC cells and peripheral blood mononuclear cells (PBMCs) treated with metformin or IL-6. In an in vivo assay, we used a model established with NPIdKO™ mice, which have a reconstituted immune system generated by transplanting PBMCs through intravenous injection, to evaluate the effect of metformin on tumors.
Results:
The TCGA esophageal cancer data showed that IL-6 expression was positively correlated with PD-L1 expression and that patients with high IL-6 expression had a significantly lower overall survival rate than patients with low IL-6 expression. PD-L1 expression in ESCC cell lines was significantly inhibited by metformin via the IL-6/JAK2/STAT3 signaling pathway but was not correlated with the canonical AMPK pathway. In the coculture system, the metformin pretreatment group showed higher T cell activation and better T cell killing function than the control group. Animal experiments confirmed that metformin downregulated PD-L1 expression and that combination treatment with metformin and PD-1 inhibitors synergistically enhanced the antitumor response.
Conclusions:
Metformin downregulated PD-L1 expression by blocking the IL-6/JAK2/STAT3 signaling pathway in ESCC, which enhanced the antitumor immune response.
Insights
Metformin inhibits PD-L1 expression in esophageal cancer by blocking the IL-6/JAK2/STAT3 pathway, enhancing antitumor immunity. This improves T cell function and tumor response, especially with PD-1 inhibitors.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Esophageal squamous cell carcinoma (ESCC) is a significant global health concern.
- Programmed death-ligand 1 (PD-L1) is a key immune checkpoint target in cancer therapy.
- Metformin's role in modulating PD-L1 expression and antitumor immunity in ESCC requires further elucidation.
Purpose of the Study:
- To investigate the mechanism by which metformin reduces PD-L1 expression in ESCC.
- To assess metformin's impact on the antitumor immune response in ESCC.
- To explore the therapeutic potential of metformin in combination with PD-1 inhibitors.
Main Methods:
- Analysis of The Cancer Genome Atlas (TCGA) database for IL-6, prognosis, and PD-L1 correlations in esophageal cancer.
- In vitro studies using RT-PCR, Western blotting, and immunofluorescence to determine metformin's effect on PD-L1 expression via the IL-6/JAK2/STAT3 pathway.
- Coculture assays with ESCC cells and peripheral blood mononuclear cells (PBMCs) to evaluate T cell function.
- In vivo studies using a humanized mouse model to assess metformin's antitumor effects and combination therapy with PD-1 inhibitors.
Main Results:
- TCGA data revealed a positive correlation between IL-6 and PD-L1 expression, with high IL-6 linked to poorer survival.
- Metformin significantly inhibited PD-L1 expression in ESCC cell lines through the IL-6/JAK2/STAT3 pathway, independent of the AMPK pathway.
- Metformin treatment enhanced T cell activation and cytotoxic function in vitro.
- In vivo experiments confirmed metformin's ability to downregulate PD-L1 and demonstrated synergistic antitumor effects when combined with PD-1 inhibitors.
Conclusions:
- Metformin effectively downregulates PD-L1 expression in ESCC by inhibiting the IL-6/JAK2/STAT3 signaling pathway.
- Metformin enhances the antitumor immune response in ESCC by improving T cell function.
- Combination therapy with metformin and PD-1 inhibitors shows significant promise for synergistic antitumor effects in ESCC.
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