Are miR-17/miR-21 the novel targets for cancer therapy by means of the blockade of long-lasting and extensional responses of tumor-associated macrophages (TAMs) to M-CSF stimulus?

Macrophage colony-stimulating factor (M-CSF), also known as CSF-1, has a broad range of actions on myeloid cell maturation, including the regulation of macrophage differentiation, proliferation, and survival. In response to M-CSF, alternatively activated or M2-like macrophages are generated. M-CSF overproduction is commonly found in tumors microenvironment. It triggers tumor growth and aggressiveness by enhancing pro-tumor activities of tumor-associated macrophages (TAM). Our recent study demonstrated that M-CSF signaling may act long-lastingly in M2 macrophages, albeit the temporal interaction of M-CSF and its receptor. Under the long-lasting effect of M-CSF in M2 macrophages, high-level expression of PD-L1 as a pro-tumor activity was maintained. The phenomenal increases of miR-17-5p and miR-21-5p expression in M2 macrophages were also observed. Surprisingly, the expression of PD-L1 was attenuated successfully by the suppression of miR-21 activity in M2 macrophages using anti-sense oligonucleotide. Furthermore, significantly phenotypical changes in M2 macrophages responding to additional IL-4 and IL10 stimuli were manifested, mainly on the upregulation of interferon regulatory factor 4 (IRF4) and downregulation of Arginase-1 and MERTK, while they had received long-lasting effect of M-CSF. Hence, we defined it as feedback from the extensional effects of M-CSF in M2 macrophages and those mechanisms are pending to be explored possibly via transcriptome profiling.