Journal
IMMUNITY
Volume 38, Issue 6, Pages 1236-1249Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2013.06.004
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Funding
- Italian Ministry of Education, University and Research [RBAP11T3WB_003, 2009NREAT2_003]
- Italian Association for Cancer Research (AIRC) [IG10400, 12182, AGIMM 100005, 6599]
- AIRC-Cariparo
- BMBF [01KU1214B]
- OBIHEP [360365]
- Fondazione Telethon Funding Source: Custom
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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. Tumorreleased cytokines signaling through gp130, the common subunit of the interleukin-6 cytokine receptor family, induced the LAP* isoform of C/EBP beta transcription factor, promoting macrophage generation. miR-142-3p downregulated gp130 by canonical binding to its messenger RNA (mRNA) 3' UTR and repressed C/EBP beta 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.
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