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トピック - 【基礎研究】Evaluation of the potential therapeutic benefits of macrophage reprogramming in multiple myeloma.

書誌情報:Gutiérrez-González A,et al. 2016  Sep 13. [Epub ahead of print]  Pubmed

カテゴリー:基礎研究


Abstract:
Tumor associated macrophages (TAM) are important components of the multiple myeloma (MM) microenvironment that support malignant plasma cell survival and resistance to therapy. It has been proposed that macrophages (MØ) retain the capacity to change in response to stimuli that can restore their antitumor functions. Here we investigated several approaches to reprogram MØ as a noveltherapeutic strategy in MM. First, we found tumor-limiting and tumor-supporting capabilities for monocyte-derived M1-like MØ and M2-like MØ, respectively, when mixed with MM cells, both in vitro and in vivo. Multicolor confocal microscopy revealed that MM associated MØ displayed a predominant M2-like phenotype in the bone marrow of MM patient samples, and a high expression of the pro-M2 cytokine macrophage migration inhibitory factor (MIF). To reprogram the pro-tumoral M2-like MØ present in MM towards anti-tumoral M1-like MØ we tested the pro-M1 cytokine GM-CSF plus blockade of the M2 cytokines M-CSF or MIF. The combination of GM-CSF plus the MIF inhibitor 4-IPP achieved the best reprogramming responses towards an M1 profile, both at gene and protein expression levels, as well as remarkable tumoricidal effects. Furthermore, this combined treatment elicited macrophage-dependent therapeuticresponses in MM xenograft mouse models, which were linked to up-regulation of M1 and reciprocal down-regulation of M2macrophage markers. Our results reveal the therapeutic potential of reprogramming macrophages in the context of MM.

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