AMPK/mTOR signaling pathway attenuates subtype-selective differentiation of Myeloid-Derived Suppressor Cells (MDSC) 

Abstract

Myeloid-Derived Suppressor Cells (MDSCs) are generated during tumor-bearing condition, and inhibit T-cell activity to promote cancer growth. Therefore, drugs which can inhibit MDSCs are new predictive immunotherapeutic medicines. On the other hand, AMP-activated protein kinase (AMPK) and mTOR signaling plays not only important role in energy homeostasis, but also recently revealed to plays a central role in an anti-tumor response. In this study, we examined the effect of metformin, an AMPK activator, and rapamycin, an inhibitor of mTOR on MDSCs differentiation. Bone marrow cells were isolated from of C57BL/6J mice and differentiated into MDSCs by the treatment with IL-6 and GM-CSF. Both metformin and rapamycin dose-dependently decreased differentiated MDSCs. These drugs also decreased the suppressing ability of MDSCs on T cell proliferation. Interestingly, subtype analysis of MDSC has shown that, these drugs decreased the ratio of monocytic MDSCs (M-MDSCs), whereas that of granulocytic MDSCs (G-MDSCs) was increased. Taken together, we assume that activation of AMPK and following inhibition of mTOR selectively inhibits M-MDSCs differentiation, and their immunosuppressive property. We expect that this study will provide new insights into the pharmacological regulation tumor immunology.