The CXCR3 targeting chemokine CXCL11 has potent antitumor activity in vivo involving attraction of CD8+ T lymphocytes but not inhibition of angiogenesis.
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.
Department of Dermatology, Leiden University Medical Center, 7333 AL Leiden, The Netherlands.
Paul J
PJ
Hensbergen
Pepijn G J T B
PG
Wijnands
Marco W J
MW
Schreurs
Rik J
RJ
Scheper
Rein
R
Willemze
Cornelis P
CP
Tensen
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054371:Chemokine CXCL11; D019743:Chemokines, CXC / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D004727:Endothelium / Q000473:pathology; D005260:Female; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D008212:Lymphocyte Depletion; D016399:Lymphoma, T-Cell / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000276:immunology* / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D014162:Transfection
C515202:CXCL11 protein, human; C515187:CXCR3 protein, human; D054371:Chemokine CXCL11; D019743:Chemokines, CXC; C515203:Cxcl11 protein, mouse; C515188:Cxcr3 protein, mouse; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D007371:Interferon-gamma