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

Abstract

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. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.