Anti‐ IL ‐6 receptor m A b eliminates myeloid‐derived suppressor cells and inhibits tumor growth by enhancing T ‐cell responses

CD 11b + G r‐1 + immature myeloid cells ( I m C s), which are abnormally increased in tumor‐bearing mice, were classified into three different subsets according to their phenotypic and morphological characteristics: G r‐1 low F 4/80 + macrophages ( M Φ‐ I m C s), G r‐1 mid stab neutrophils ( N eut stab ‐ I m C s), and G r‐1 high segmented neutrophils ( N eut seg ‐ I m C s). In the spleen, only M Φ‐ I m C s but not N eut stab ‐ I m C s and N eut seg ‐ I m C s exhibited a significant immunosuppressive activity in MLR . In contrast, tumor‐infiltrating leukocytes ( TIL s) contained only two I m C subsets, M Φ‐ I m C s and N eut seg ‐ I m C , both of which exhibited stronger inhibitory activity against T cells compared with spleen‐ M Φ‐ I m C s. Thus, we concluded that tumor‐infiltrating M Φ‐ I m C s and N eut seg ‐ I m C s were fully differentiated myeloid‐derived suppressor cells ( MDSC s) with stronger T ‐cell inhibitory activity. Indeed, spleen M Φ‐ I m C s were converted into stronger M Φ‐ MDSC s by tumor‐derived factor ( TDF ). Moreover, both spleen N eut stab ‐ I m C s and N eut seg ‐ I m C s differentiated into N eut seg ‐ MDSC s with suppressive activity after culture with TDF . We first demonstrated that administration of anti‐ IL ‐6 R m A b could downregulate the accumulation of M Φ‐ MDSC s and N eut seg ‐ MDSC s in tumor‐bearing mice. The elimination of those MDSC s caused subsequent enhancement of antitumor T ‐cell responses, including IFN ‐γ‐production. The therapeutic effect of anti‐ IL ‐6 R m A b was further enhanced by combination with gemcitabine ( GEM ). Thus, we propose that anti‐ IL ‐6 R m A b could become a novel tool for the downmodulation of MDSC s to enhance antitumor T‐cell responses in tumor‐bearing hosts.