Indoleamine-2,3-dioxygenase in an immunotherapy model for Ewing sarcoma

Anticancer Res. 2014 Nov;34(11):6431-41.


Background/aim: Interleukin-2 (IL2) transgenic Ewing sarcoma cells reduce tumor growth in vivo and in vitro. In the present study we analyzed the expression of immune suppressive indoleamine-2,3-dioxygenase (IDO) in this model.

Materials and methods: Expression of IDO was analyzed by polymerase chain reaction. The impact of the cluster of differentiation 137 (CD137)/CD137 ligand (CD137L) co-stimulatory system on expression of IDO and different cytokines was analyzed both in vivo and in vitro.

Results: Tumors that developed in vivo in the presence of IL2 transgenic tumor cells expressed IDO. The presence of CD137L transgenic tumor cells led to down-regulation of IDO. Further in-vitro analysis of this phenomenon indicated that IDO was expressed in tumor cells as a consequence of interferon-gamma produced by lymphocytes in response to IL2. Depending on the concentration of IL2, stimulation of CD137 increased or reduced cytokine production in lymphocytes.

Conclusion: Our data indicate that the CD137/CD137L pathway can modulate the immune response against Ewing sarcoma cells.

Keywords: CD137; Ewing sarcoma; Interleukin-2; immune escape; indoleamine-2,3-dioxygenase.

MeSH terms

  • Animals
  • Bone Neoplasms / enzymology
  • Bone Neoplasms / immunology
  • Bone Neoplasms / therapy*
  • Cytokines / genetics
  • Cytokines / metabolism
  • Disease Models, Animal
  • Flow Cytometry
  • Humans
  • Immunotherapy*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism*
  • Interferon-gamma / pharmacology*
  • Interleukin-2 / physiology*
  • Lymphocytes / enzymology
  • Lymphocytes / immunology
  • Lymphocytes / pathology
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Mice, Transgenic
  • OX40 Ligand / genetics
  • OX40 Ligand / metabolism
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sarcoma, Ewing / enzymology
  • Sarcoma, Ewing / immunology
  • Sarcoma, Ewing / therapy*
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / genetics
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / metabolism
  • Xenograft Model Antitumor Assays


  • Cytokines
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Interleukin-2
  • OX40 Ligand
  • RNA, Messenger
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Interferon-gamma