miR-142-3p Prevents Macrophage Differentiation during Cancer-Induced Myelopoiesis

Abstract

Tumor progression is accompanied by an altered myelopoiesis causing the accumulation of immunosuppressive cells. Here, we showed that miR-142-3p downregulation promoted macrophage differentiation and determined the acquisition of their immunosuppressive function in tumor. Tumor-released cytokines signaling through gp130, the common subunit of the interleukin-6 cytokine receptor family, induced the LAP∗ isoform of C/EBPβ transcription factor, promoting macrophage generation. miR-142-3p downregulated gp130 by canonical binding to its messenger RNA (mRNA) 3' UTR and repressed C/EBPβ LAP∗ by noncanonical binding to its 5' mRNA coding sequence. Enforced miR expression impaired macrophage differentiation both in vitro and in vivo. Mice constitutively expressing miR-142-3p in the bone marrow showed a marked increase in survival following immunotherapy with tumor-specific T lymphocytes. By modulating a specific miR in bone marrow precursors, we thus demonstrated the feasibility of altering tumor-induced macrophage differentiation as a potent tool to improve the efficacy of cancer immunotherapy.

Dendritic cell-mediated survival signals in Eμ-Myc B-cell lymphoma depend on the transcription factor C/EBPβ

“…For MDSCs and tumour-associated macrophages in solid tumours, a contextual regulation of C/EBPb activity favouring an immunosuppressive environment has been suggested 16,60 .…”

Cell‐to‐cell communication: microRNAs as hormones

“…(Sonda et al . (2013) identified 79 differentially expressed miRNAs in either tumor‐infiltrating versus normal CD11b + cells purified from the spleen of healthy mice. They found that miR‐142‐3p and miR‐150 were the most downregulated miRNAs in tumor‐infiltrating CD11b + cells and computationally determined genes that are involved in monocyte–macrophage commitment, as well as potential target genes of miR‐142‐3p (Sonda et al ., 2013).…”

“…They found that miR‐142‐3p and miR‐150 were the most downregulated miRNAs in tumor‐infiltrating CD11b + cells and computationally determined genes that are involved in monocyte–macrophage commitment, as well as potential target genes of miR‐142‐3p (Sonda et al ., 2013). They further showed that miR‐142‐3p directly regulates gp130, which is a common subunit of the interleukin‐6 cytokine receptor family that regulates macrophage generation (Sonda et al ., 2013). A comprehensive list of extracellular miRNAs shuttling between cancer cells and their neighboring cells can be found in Table 1.…”

Mature T cell responses are controlled by microRNA-142

“…The complete KO animals generated by us did not show any defects in numbers of HSCs when compared with WT animals (data not shown). Recent data have suggested a role for miR-142 in other hematopoietic-derived cell functions, such as regulatory T cell function (19), myeloid cell differentiation (9,12,13), and megakaryopoiesis (14). Furthermore, in association with other aberrations, it has also been incriminated in the development of hematopoietic malignancies (16,17) and even nonhematopoietic cells and malignancies (18,36).…”

“…miR-142 regulates innate immunity by negatively regulating IL-6 expression in DCs (9), and a recent study indicated that miR-142-3p plays critical roles in the maintenance of CD4 + DCs (12). Recent studies have also demonstrated that miR-142-3p prevents macrophage differentiation during tumor-induced myeloid differentiation (13) and megakaryopoiesis (14). But its role in adaptive immunity, specifically for naive T cell development and function, remains unknown.…”