Rapamycin downregulates NKG2D ligands in acute myeloid leukemia cells via an activation of the STAT3 pathway: a potential mechanism for rapamycin-induced immune escape in leukemia

Zhichao Zhu, Yu Bai, Xuzhang Lu, Jun Ding, Chunjian Qi


Background: The constitutive activation of the mammalian target of rapamycin (mTOR) is involved in the pathogenesis of many cancers. Rapamycin (RAPA), a specific inhibitor of mTOR, has been applied to the clinical treatment of tumors, and its anti-leukemia effect has also been confirmed.
Methods: We detected apoptosis and the NKG2D ligands expression in acute myeloid leukemia (AML) cells using flow cytometry and investigated the cytotoxicity of AML cells that had been co-cultured with natural killer (NK) cells using CFSE staining. We evaluated the signal pathways with a western blot assay.
Results: In this study, we found that RAPA can significantly inhibit the proliferation of AML cells. Further studies showed that the use of RAPA alone reduced the expression of NKG2D ligands on the membranes of HL-60 and THP-1 AML cells. Also, RAPA blocked the upregulation of the NKG2D ligand when AML cells were cultured with the demethylation drug decitabine (DAC). We found that RAPA decreased the expression of the NKG2D ligands by inducing the STAT3 phosphorylation of AML cells.
Conclusions: The discovery of this mechanism might further optimize the clinical use of RAPA for the treatment of AML.