Apoptotic tumor cells induce IL-27 release from human DCs to activate Treg cells that express CD69 and attenuate cytotoxicity

Eur J Immunol. 2012 Jun;42(6):1585-98. doi: 10.1002/eji.201142093.


Intrinsic immunosuppression is a major obstacle for successful cancer therapy. The mechanisms for the induction and regulation of immunosuppression in humans are ill defined. A microenvironmental component that might prevent antitumor immunity is the presence of dying tumor cells, which are abundant following conventional cancer ablation methods such as chemo- or radiotherapy. Shedding of apoptotic debris and/or secretion of factors to the tumor bed or draining lymph nodes thus might have a profound impact on professional phagocytes, such as DCs, and subsequent priming of lymphocytes. Here, we exposed human DCs to supernatants of live, apoptotic, or necrotic human breast cancer cells and cocultured them with autologous T cells. Priming with apoptotic debris prevented DCs from establishing cytotoxicity toward live human tumor cells by inducing a Treg-cell population, defined by coexpression of CD39 and CD69. Immunosuppression via Treg cells was transferable and required the release of sphingosine-1-phosphate (S1P) from apoptotic cells, acting via S1P receptor 4 on DCs to induce IL-27 secretion. We propose that CD69 expression on CD39(+) Treg cells enables them to interact with CD73-expressing CD8(+) T cells to generate adenosine, thereby suppressing cytotoxicity. These findings aid the understanding of how dying tumor cells limit antitumor immunity.

Publication types

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

MeSH terms

  • Adenosine / biosynthesis
  • Antigens, CD / analysis
  • Antigens, CD / physiology*
  • Antigens, Differentiation, T-Lymphocyte / analysis
  • Antigens, Differentiation, T-Lymphocyte / physiology*
  • Apoptosis*
  • Apyrase / analysis
  • Cell Line, Tumor
  • Cytotoxicity, Immunologic*
  • Dendritic Cells / immunology*
  • Female
  • Forkhead Transcription Factors / analysis
  • Humans
  • Interleukins / physiology*
  • Lectins, C-Type / analysis
  • Lectins, C-Type / physiology*
  • Lymphocyte Activation*
  • Neoplasms / immunology
  • Neoplasms / pathology*
  • Receptors, Lysosphingolipid / physiology
  • T-Lymphocytes, Regulatory / immunology*


  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • CD69 antigen
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Interleukins
  • Lectins, C-Type
  • MYDGF protein, human
  • Receptors, Lysosphingolipid
  • Apyrase
  • CD39 antigen
  • Adenosine