Interleukin‐6/<scp>STAT</scp>3 signaling as a promising target to improve the efficacy of cancer immunotherapy

Abstract

Overcoming the immunosuppressive state in tumor microenvironments is a critical issue for improving 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 ( DC ) through activation of signal transducer and activator of transcription 3 ( STAT 3). Thus, we focused on the precise effect of the IL ‐6/ STAT 3 signaling cascade on human DC and the subsequent induction of antitumor T cell immune responses. Tumor‐infiltrating CD 11b + CD 11c + 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 STAT 3 activation reduced surface expression of HLA ‐ DR on CD 14 + monocyte‐derived DC . 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 DC . These findings suggest that IL ‐6‐mediated STAT 3 activation in the tumor microenvironment inhibits functional maturation of DC to activate effector T cells, blocking introduction of antitumor immunity in cancers. Therefore, we propose in this review that blockade of the IL ‐6/ STAT 3 signaling pathway and target molecules in DC may be a promising strategy to improve the efficacy of immunotherapies for cancer patients.