Journal
JOURNAL OF IMMUNOTHERAPY
Volume 28, Issue 4, Pages 343-351Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/01.cji.0000165355.26795.27
Keywords
CXCR3 targeting chemokines; angiogenesis; in vivo antitumor activity; mouse model; CD8(+) T cells; EL-4 lymphoma cells
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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 CXCL 10 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.
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