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Immunology |
Departments of Surgery [M. H., K. H., M. T. L., H. T.], Molecular Genetics and Biochemistry [M. H., P. D. R., M. T. L., H. T.], and Cell Biology and Physiology [S. C. W.], School of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, and Department of Molecular Preventive Medicine, School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113, Japan [N. O., K. M.]
Dendritic cells (DCs) are very potent antigen-presenting cells
and play critical roles in regulating immune responses in cancer. The
migrating of DCs from the tumor site to the lymphoid organs is believed
to be one of the critical events. To examine this important DC function
in tumor situations, bone marrow-derived DCs, cultured for 6 days with
granulocyte macrophage colony-stimulating factor and interleukin 4,
were inoculated at the tumor site. We have shown (Y. Nishioka
et al., Cancer Res., 59: 4035–4041,
1999) that DCs can migrate from tumor site to the draining lymph nodes
within 24 h (
0.1% of administrated DCs). The DCs then form
clusters with adjacent lymphoid cells, which produce IFN-
(1500–3200pg/106cells/48 h) in response to tumor
stimulation. The number of the DCs migrating into lymph nodes were
greater when they were inoculated into the tumor rather than the skin.
Coculture of DCs and apoptotic tumor cells resulted in decreased
expression of CC chemokine receptor (CCR) 1 and increased CCR7
expression at mRNA level without alteration in other phenotypical
markers on DCs. Chemotaxis assay showed that CCR7 ligands, macrophage
inflammatory protein 3ß and secondary lymphoid-tissue chemokine
significantly (P < 0.05) induced the
migration of DCs when cocultured with apoptotic tumor cells. To
directly examine the involvement of CCR7 expression in DC migration, we
investigated the functions of DCs genetically modified to express high
levels of CCR7. CCR7 transduction promotes DC migration in response to
relevant ligands in vitro and in vivo.
These results suggest that the CCR7 expression of DCs is enhanced with
direct contact with apoptotic tumor cells and may have a critical role
for DC migrating to regional lymph nodes. The means to promote DC
delivery to tumor and to nodal sites represent novel targets for the
biological therapy of cancer.
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