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

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-1low F4/80+ macrophages (MF-ImCs), Gr-1mid stab neutrophils (Neutstab-ImCs), and Gr-1high segmented neutrophils (Neutseg-ImCs). In the spleen, only MF-ImCs but not Neutstab-ImCs and Neutseg-ImCs exhibited a significant immunosuppressive activity in MLR. In contrast, tumor-infiltrating leukocytes (TILs) contained only two ImC subsets, MF-ImCs and Neutseg-ImC, both of which exhibited stronger inhibitory activity against T cells compared with spleen-MF-ImCs. Thus, we concluded that tumor-infiltrating MF-ImCs and Neutseg-ImCs were fully differentiated myeloid-derived suppressor cells (MDSCs) with stronger T-cell inhibitory activity. Indeed, spleen MF-ImCs were converted into stronger MF-MDSCs by tumor-derived factor (TDF). Moreover, both spleen Neutstab-ImCs and Neutseg-ImCs differentiated into Neutseg-MDSCs with suppressive activity after culture with TDF. We first demonstrated that administration of anti-IL-6R mAb could downregulate the accumulation of MF-MDSCs and Neutseg-MDSCs in tumor-bearing mice. The elimination of those MDSCs caused subsequent enhancement of antitumor T-cell responses, including IFN-?-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.