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Eur J Immunol. 2012 Aug;42(8):2060-72. doi: 10.1002/eji.201142335.

Anti-IL-6 receptor mAb eliminates myeloid-derived suppressor cells and inhibits tumor growth by enhancing T-cell responses.

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Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.


CD11b(+) Gr-1(+) immature myeloid cells (ImCs), which are abnormally increased in tumor-bearing mice, were classified into three different subsets according to their phenotypic and morphological characteristics: Gr-1(low) F4/80(+) macrophages (MΦ-ImCs), Gr-1(mid) stab neutrophils (Neut(stab)-ImCs), and Gr-1(high) segmented neutrophils (Neut(seg)-ImCs). In the spleen, only MΦ-ImCs but not Neut(stab)-ImCs and Neut(seg)-ImCs exhibited a significant immunosuppressive activity in MLR. In contrast, tumor-infiltrating leukocytes (TILs) contained only two ImC subsets, MΦ-ImCs and Neut(seg)-ImC, both of which exhibited stronger inhibitory activity against T cells compared with spleen-MΦ-ImCs. Thus, we concluded that tumor-infiltrating MΦ-ImCs and Neut(seg)-ImCs were fully differentiated myeloid-derived suppressor cells (MDSCs) with stronger T-cell inhibitory activity. Indeed, spleen MΦ-ImCs were converted into stronger MΦ-MDSCs by tumor-derived factor (TDF). Moreover, both spleen Neut(stab)-ImCs and Neut(seg)-ImCs differentiated into Neut(seg)-MDSCs with suppressive activity after culture with TDF. We first demonstrated that administration of anti-IL-6R mAb could downregulate the accumulation of MΦ-MDSCs and Neut(seg)-MDSCs in tumor-bearing mice. The elimination of those MDSCs caused subsequent enhancement of antitumor T-cell responses, including IFN-γ-production. The therapeutic effect of anti-IL-6R mAb was further enhanced by combination with gemcitabine (GEM). Thus, we propose that anti-IL-6R mAb could become a novel tool for the downmodulation of MDSCs to enhance antitumor T-cell responses in tumor-bearing hosts.

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