Pro-inflammatory chemokine-chemokine receptor interactions within the Ewing sarcoma microenvironment determine CD8(+) T-lymphocyte infiltration and affect tumour progression

J Pathol. 2011 Feb;223(3):347-57. doi: 10.1002/path.2819. Epub 2010 Dec 10.


Ewing sarcoma is an aggressive round cell sarcoma with poor patient prognosis, particularly in cases of advanced-stage disease. Dynamic tumor-host immune interations within the tumor microenvironment may polarize in situ immune responses and shape tumor development and/or progression. To gain insight into the nature of tumour-host immune interactions within the Ewing sarcoma microenvironment, the presence and spatial distribution of infiltrating CD8(+) /CD4(+) T-lymphocytes were evaluated in therapy-naive Ewing sarcoma. Expression profiling of 40 different chemokines and several chemokine receptors was performed in therapy-naive tumours and cell lines by qPCR, immunohistochemistry, and flow cytometry. Considerable inter-tumour variation was observed regarding density, type, and distribution of infiltrating T-lymphocytes. Tumour-infiltrating T-cells contained significantly higher percentages of CD8(+) T-lymphocytes as compared to stroma-infiltrating cells, suggesting preferential migration of this T-cell type into tumour areas. Gene expression levels of several type 1-associated, pro-inflammatory chemokines (CXCR3- and CCR5-ligands CXCL9, CXCL10, and CCL5) correlated positively with infiltrating (CD8(+) ) T-lymphocyte numbers expressing corresponding chemokine receptors. Survival analyses demonstrated an impact of tumour-infiltrating, and not stroma-infiltrating, CD8(+) T-lymphocytes on tumour progression. At protein level, both tumour and stromal cells expressed the IFNγ-inducible chemokines CXCL9 and CXCL10. CCR5-ligand CCL5 was exclusively expressed by non-tumoural stromal/infiltrating cells. Together, our results indicate that an inflammatory immune microenvironment with high expression of type 1-associated chemokines may be critical for the recruitment of (CD8(+) ) T-lymphocytes expressing corresponding chemokine receptors. The observed impact of tumour-infiltrating (CD8(+) ) T-lymphocytes is consistent with a role for adaptive anti-tumour immunity in the prevention of Ewing sarcoma progression. Recognition of the merits and exploitation/induction of an inflammatory microenvironment may improve the efficacy of natural immune responses against, and (adoptive) immunotherapeutic approaches for, Ewing sarcoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Bone Neoplasms / immunology*
  • CD8-Positive T-Lymphocytes / immunology
  • Child
  • Child, Preschool
  • Disease Progression
  • Gene Expression Profiling / methods
  • Humans
  • Inflammation Mediators / metabolism*
  • Interferon-gamma / biosynthesis
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Neoplasm Proteins / metabolism
  • Polymerase Chain Reaction / methods
  • Receptors, CCR5 / metabolism
  • Receptors, CXCR3 / metabolism
  • Receptors, Chemokine / metabolism*
  • Sarcoma, Ewing / immunology*
  • Tumor Cells, Cultured
  • Tumor Microenvironment / immunology


  • CXCR3 protein, human
  • Inflammation Mediators
  • Neoplasm Proteins
  • Receptors, CCR5
  • Receptors, CXCR3
  • Receptors, Chemokine
  • Interferon-gamma