Effect of miR-142-3p on the M2 Macrophage and Therapeutic Efficacy Against Murine Glioblastoma

Profound immune suppression exists in the glioblastoma microenvironment that promotes glioma invasion and progression and systemically inhibits antitumor immunity. MicroRNAs (miRNAs) are noncoding molecules involved in post-transcriptional gene regulation that have been shown to modulate tumor cell proliferation and apoptosis and to act as oncogenes or tumor-suppressor genes (1,2). miR-142-3p has been shown to be a useful biomarker and potential therapeutic target in a variety of malignancies (3–6). Although most studies on miR-142-3p focus on expression frequency or prognostic impact, emerging data indicate that miR-142-3p is involved in immunological reactivity and activation (7–9), including T-cell immune suppression (10–12). Moreover, miR142-3p may influence the differentiation state of immune cell populations (13,14). Tumor-associated macrophages, the largest infiltrating immune cell population in glioblastomas (15), originate from the peripheral blood monocytes and are recruited by a variety of tumor-derived signals. Glioblastomas actively recruit circulating macrophages to the tumor site and induce them to adopt a tumor-supportive M2 phenotype capable of mediating immune suppression and promoting invasion (16). This shift away from the desired proinflammatory/antitumor M1 phenotype (17) by cytokines such as transforming growth factor beta (TGF-β) may be regulated by miR-142-3p (14,18,19). Although the immune suppressive properties of glioblastoma-infiltrating macrophages have been investigated, the relationship to miRNA dysregulation has not been evaluated to date. Therefore, we hypothesized that miR-142-3p, by interacting with the TGF-β pathway, regulates the tumor-supportive properties of glioma-associated macrophages and potent antitumor immune effects can be exerted by manipulating miR-142-3p levels in vivo.