The CXCR3 targeting chemokine CXCL11 has potent antitumor activity in vivo involving attraction of CD8+ T lymphocytes but not inhibition of angiogenesis

J Immunother. Jul-Aug 2005;28(4):343-51. doi: 10.1097/01.cji.0000165355.26795.27.

Abstract

The IFN-gamma-inducible and CXCR3-targeting human CXC chemokines CXCL9 (Mig) and CXCL10 (IP10) have potent antitumor activity through attraction of cytotoxic T lymphocytes and inhibition of angiogenesis. The more recently identified CXCR3-targeting chemokine CXCL11 (I-TAC/IP9) proved to be a more potent chemokine than CXCL9 and CXCL10 in vitro, both in chemotaxis assays with CXCR3+ T lymphocytes and in calcium mobilization experiments. However, its antitumor activity in vivo has not been shown so far. To investigate this, mice were challenged with EL4 T-cell lymphoma cells, genetically modified to produce murine CXCL11. Tumor growth curves showed complete rejection of CXCL11-producing tumors but not of control tumors. Tumor infiltrate analysis by flow cytometry showed a clear correlation between rejection of CXCL11-producing tumors and an increase of tumor-infiltrating CD8+CXCR3+ as well as CD8+CXCR3- T lymphocytes. In vivo CD8 T-cell depletion completely abrogated the antitumor effect. No difference in angiogenesis between control and CXCL11-producing tumors was observed. In survivors, rechallenge experiments with wild-type tumor cells suggested development of protective antitumor immunity involving tumor-specific IFN-gamma production by CD8+ T lymphocytes. These experiments show, for the first time, antitumor activity of CXCL11 in vivo, which warrants exploration for its potential role in anticancer immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / pathology
  • Cell Count
  • Cell Line, Tumor
  • Cell Proliferation
  • Chemokine CXCL11
  • Chemokines, CXC / genetics
  • Chemokines, CXC / immunology*
  • Chemokines, CXC / metabolism
  • Chemotaxis, Leukocyte / immunology*
  • Endothelium / pathology
  • Female
  • Humans
  • Immunologic Memory / immunology
  • Interferon-gamma / metabolism
  • Lymphocyte Depletion
  • Lymphoma, T-Cell / immunology*
  • Lymphoma, T-Cell / pathology
  • Macrophages / cytology
  • Macrophages / immunology
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Pathologic / immunology*
  • Neovascularization, Pathologic / pathology
  • Platelet Endothelial Cell Adhesion Molecule-1 / analysis
  • Receptors, CXCR3
  • Receptors, Chemokine / immunology*
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology
  • Transfection

Substances

  • CXCL11 protein, human
  • CXCR3 protein, human
  • Chemokine CXCL11
  • Chemokines, CXC
  • Cxcl11 protein, mouse
  • Cxcr3 protein, mouse
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Receptors, CXCR3
  • Receptors, Chemokine
  • Interferon-gamma