Manipulating microRNAs to regulate macrophage polarization in gliomas.

Tumor associated macrophages (TAMs) play a critical role in solid tumor development where they regulate neoplastic cell proliferation , survival and invasion, promote angiogenesis, and impact effector functions of T cells (1). Typically, TAMs activated by toll-like receptor (TLR) signaling or interferon (IFN)-γ are considered classically activated or Th1-type cells, whereas those activated by interleukin (IL)-4/13 or IL-10 are characterized as alternatively activated Th2-type macrophages (2). Although these are simplistic descriptions of a complex heterogenous and dynamic population of myeloid cells in tumors, these variably polarized states enable a broad understanding into how these important cells provide either a restrictive (antitumor) or permissive (protumor) environment regulating tumor progression (1). Notably, functional significance of TAMs in several tumor types (breast, melanoma, and pancreas) has recently been revealed (3–5), as well as in glioma, wherein functional reprograming of TAMs via blockade of colony-stimulating factor-1 receptor (CSF1R) markedly limits tumor development (6). MicroRNAs (miRs) are small, 20–24 nucleotide-long RNAs that regulate gene expression by binding to mRNAs (7). miRs represent approximately 1% to 2% of genes in several species, including mammals. Current estimates indicate that the human genome contains 1872 miR precursors that are processed into 2578 mature miRs (1186 precursors processed into 1908 mature miRs in mouse). Accordingly, miRs have been found to play a role in regulating essentially all physiological and pathological processes in mammals, including functions of TAMs (8–10). In this issue of the Journal, Xu et al. (11) reveal the role of a specific miR, miR-142-3p, in regulating TAM polarization and thus function in glioblastoma. The authors identified dysregulated miRs in the glioma tumor microenvironment (TME) by comparing miR profiles of TAMs and monocytes derived from glioblastoma patients vs healthy donors. Their results identified miR-142-3p as being statistically significantly downregulated in glioma-associated TAMs as compared with monocytes. Experimentally, the authors addressed the funtional significance of this observation by revealing that ectopic expression of miR-142-3p led to downregulation of transforming growth factor beta receptor I (TGFβRI) in vitro in Th2-but not Th1-type TAMs, thus leading to cell death. Based on higher levels of miR-142-3p expression in Th1-polarized TAMs, the authors postulated that repression of miR-142-3p actively fostered Th2 polarization and TAM survival, and thus hypotheszied miR-142-3p targeting as a therapeutic strategy to reduce presence of protumoral TAMs in glioma. Indeed, the authors demonstrated that treatment of mice with miR-142-3p decreased tumor burden and survival in subcutanous and orthotopic models of …