The proinflammatory cytokine IL-6 activates STAT3 signaling in dendritic cells, reducing antigen presentation via downregulation of MHC class II/HLA-DR (by degradation within the lysosome), and attenuates Th1 CD4+ responses via reduced IL-12 production. The data, thoroughly reviewed by Kitamura et al., suggest that blockade of IL-6 signaling is a promising target for cancer immunotherapy.

Overcoming the immunosuppressive state in tumor microenvironments is a critical issue to improve the efficacy of cancer immunotherapy. Interleukin (IL)-6, a pleiotropic cytokine, is highly produced in the tumor-bearing host. Previous studies have indicated that IL-6 suppresses the antigen presentation ability of dendritic cells (DCs) through activation of signal transducer and activator of transcription 3 (STAT3). Thus, we focused on the precise effect of the IL-6/STAT3 signaling cascade on human DCs and the subsequent induction of antitumor T cell immune responses. Tumor-infiltrating CD11b+ CD11c+ cells isolated from colorectal cancer tissues showed strong induction of the IL-6 gene, downregulated surface expression of human leukocyte antigen (HLA)-DR, and an attenuated T cell-stimulating ability compared with those from peripheral blood mononuclear cells, suggesting that the tumor microenvironment suppresses antitumor effector cells. In vitro experiments revealed that IL-6-mediated STAT3 activation reduced surface expression of HLA-DR on CD14+ monocyte-derived DCs. Moreover, we confirmed that cyclooxygenase 2, lysosome protease, and arginase activities were involved in the IL-6-mediated downregulation of the surface expression levels of HLA class II on human DCs. These findings suggest that IL-6-mediated STAT3 activation in the tumor microenvironment inhibits functional maturation of DCs to activate effector T cells, blocking introduction of antitumor immunity in cancers. Therefore, we propose in this review that blockade of the IL-6/STAT3 signaling pathway and target molecules in DCs may be a promising strategy to improve the efficacy of immunotherapies for cancer patients. This article is protected by copyright. All rights reserved.

Author Info: (1) Division of Functional Immunology, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-0815, Japan. (2) Div

Author Info: (1) Division of Functional Immunology, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-0815, Japan. (2) Division of Functional Immunology, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-0815, Japan. Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-8638, Japan. (3) Division of Functional Immunology, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-0815, Japan. Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-8638, Japan. (4) Division of Functional Immunology, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-0815, Japan. (5) Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-8638, Japan. (6) Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-8638, Japan. (7) Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-8638, Japan. (8) Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-8638, Japan.