IL-6/STAT3 signaling as a promising target to improve the efficacy of cancer immunotherapy

Abstract

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.

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