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

Cancer Sci. 2017 Oct;108(10):1947-1952. doi: 10.1111/cas.13332. Epub 2017 Aug 23.


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 (STAT3). Thus, we focused on the precise effect of the IL-6/STAT3 signaling cascade on human DC 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 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 STAT3 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/STAT3 signaling pathway and target molecules in DC may be a promising strategy to improve the efficacy of immunotherapies for cancer patients.

Keywords: Cancer immunotherapy; STAT 3; dendritic cell; immunosuppression; interleukin-6.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Cyclooxygenase 2 / metabolism
  • Dendritic Cells
  • Gene Expression Regulation, Neoplastic / drug effects
  • HLA-DR Antigens / metabolism
  • Humans
  • Immunotherapy / methods*
  • Interleukin-6 / metabolism*
  • Neoplasms / drug therapy*
  • Neoplasms / immunology
  • STAT3 Transcription Factor / genetics*
  • Signal Transduction
  • Tumor Microenvironment / drug effects


  • Antineoplastic Agents
  • HLA-DR Antigens
  • IL6 protein, human
  • Interleukin-6
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Cyclooxygenase 2
  • PTGS2 protein, human