TLR8 signaling enhances tumor immunity by preventing tumor-induced T-cell senescence

EMBO Mol Med. 2014 Oct;6(10):1294-311. doi: 10.15252/emmm.201403918.


Accumulating evidence suggests the immunosuppressive microenvironments created by malignant tumors represent a major obstacle for effective anti-tumor immunity. A better understanding of the suppressive mechanisms mediated by tumor microenvironments and the development of strategies to reverse the immune suppression are major challenges for the success of tumor immunotherapy. Here, we report that human tumor cells can induce senescence in naïve/effector T cells, exhibiting potent suppressive function in vitro and in vivo. We further show that tumor-derived endogenous cyclic adenosine monophosphate (cAMP) is responsible for the induction of T-cell senescence. Importantly, activation of TLR8 signaling in tumor cells can block the induction and reverse the suppression of senescent naïve and tumor-specific T cells in vitro and in vivo, resulting in enhanced anti-tumor immunity. These studies identify a novel mechanism of human tumor-mediated immune suppression and provide a new strategy to reverse tumor immunosuppressive effects for tumor immunotherapy.

Keywords: immunosenescence; regulatory T cells; toll‐like receptor; tumor immunity; tumor microenvironment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Line, Tumor
  • Cells, Cultured
  • Cellular Senescence / genetics
  • Cellular Senescence / immunology
  • Coculture Techniques
  • Cyclic AMP / immunology
  • Cyclic AMP / metabolism
  • Flow Cytometry
  • Humans
  • Immunotherapy, Adoptive
  • Interleukin Receptor Common gamma Subunit / deficiency
  • Interleukin Receptor Common gamma Subunit / genetics
  • MCF-7 Cells
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Neoplasms / genetics
  • Neoplasms / immunology*
  • Neoplasms / therapy
  • RNA Interference
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Toll-Like Receptor 8 / genetics
  • Toll-Like Receptor 8 / immunology*
  • Toll-Like Receptor 8 / metabolism
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology
  • Xenograft Model Antitumor Assays


  • Il2rg protein, mouse
  • Interleukin Receptor Common gamma Subunit
  • TLR8 protein, human
  • Toll-Like Receptor 8
  • Cyclic AMP