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P059 The metformin inhibits MDSC and M2 macrophage via AMPK-induced inhibition of HMG-CoA reductase in tumour microenvironment of colitic cancer

J. Y. Kang1, Y. H. Park1, S. J. Park1, J. H. Cheon1, W. H. Kim1, T. I. Kim*1

1Yonsei University College of Medicine, Internal Medicine, Seoul, South Korea

Background

MDSC (myeloid-derived suppressor cell) and M2 macrophage in tumour microenvironment contribute to tumour progression by inducing immune tolerance to tumour antigens and cancer cells. It has been reported that metformin has anti-inflammatory and anti-tumour effects. However, there is no report on the effect of metformin on inflammatory cells of tumour microenvironment and its mechanism.

Methods

THP-1 cells were used, and treated with metformin 0.25, 0.5, 1, 2.5, and 5 mM for 48 h. We performed a flow cytometry analysis, utilising surface markers such as CD33, arginase, CD206, CD163, and CD68, to estimate MDSC and M2 macrophage fraction of THP-1 cells. To investigate AMPK-mTOR and cholesterol pathway, we performed western blot analysis for p-AMPK and p-S6, and treated AICAR (AMPK activator), Compound C (AMPK inhibitor), rapamycin (mTOR inhibitor), simvastatin (HMG-CoA reductase inhibitor), and mevalonate (mediator of cholesterol metabolism).

Results

The treatment of metformin on THP-1 cells decreased the fraction of MDSC (CD33, arginase), and M2 macrophage (CD206, CD163). In the western blot analysis, metformin treatment activated p-AMPK and inhibited p-S6. The fraction of MDSC and M2 macrophage was decreased by AICAR and increased by Compound C treatment. The inhibitory effect of metformin on MDSC and M2 macrophage was reversed by Compound C and mevalonate treatment. In addition, rapamycin or simvastatin treatment to THP-1 cells also decreased the fraction of MDSC and M2 macrophage, which was reversed by mevalonate treatment. In APCmin-DSS cancer model, metformin decreased the number and volume of tumour and the number of MDSC and M2 macrophage in tumour microenvironment.

Conclusion

The inhibitory effect of metformin on MDSC and M2 macrophage in colitic cancer microenvironment is mediated by AMPK-activation-induced inhibition of HMG-CoA reductase.