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-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.
Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
Kentaro
K
Sumida
Daiko
D
Wakita
Yoshinori
Y
Narita
Kazutaka
K
Masuko
Satoshi
S
Terada
Kazue
K
Watanabe
Takayuki
T
Satoh
Hidemitsu
H
Kitamura
Takashi
T
Nishimura
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D017951:Antigen Presentation / Q000276:immunology; D039481:CD11b Antigen; D002294:Carcinoma, Squamous Cell / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D022423:Myeloid Cells / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology; D019947:Receptors, Interleukin-6 / Q000276:immunology*; D012878:Skin Neoplasms / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D000093542:Gemcitabine
D000911:Antibodies, Monoclonal; D039481:CD11b Antigen; D019947:Receptors, Interleukin-6; D003841:Deoxycytidine; D007371:Interferon-gamma; D000093542:Gemcitabine