Enhancement of anti-tumor immunity by tumor cells transfected with the secondary lymphoid tissue chemokine EBI-1-ligand chemokine and stromal cell-derived factor-1alpha chemokine genes.
Several new lymphocyte-specific chemokines, which attract naive and memory T cells, B cells, dendritic cells and natural killer cells, have been isolated. We have found evidence of the anti-tumor effects of 3 major lymphocyte-specific chemokines, secondary lymphoid tissue chemokine (SLC), EBI-1-ligand chemokine (ELC) and stromal cell-derived factor (SDF)-1alpha, in murine models (Meth A fibrosarcoma and HM-1 ovarian tumor). In both naive and immunized mice, tumors expressing SLC, ELC or SDF-1alpha showed delayed progression compared with control tumors. In mice immunized with tumor cells expressing 1 of these 3 chemokine genes, challenge with parental tumor cells resulted in slightly slower progression than in control mice, while in mice immunized with tumor cells transfected to co-express IL-2 or granulocyte-macrophage colony-stimulating factor (GM-CSF) as well as these chemokines, all tumors regressed. Furthermore, spleen cells from mice immunized with these "double-transfected" tumor cells exhibited higher proliferative responses and greater cytotoxic activity against parental tumor cells. These anti-tumor effects were associated with profound alterations in the leukocyte populations within the tumors and regional lymph nodes, and this was due to activation of type I T cell-dependent responses that produced high levels of IFN-gamma. These findings show that SLC, ELC and SDF-1alpha enhance anti-tumor immunity both systemically and locally and that these chemokines may be clinically useful, especially when combined with IL-2 and GM-CSF.
First Department of Internal Medicine, Ehime University School of Medicine, Shigenobu, Ehime, Japan.
T
T
Nomura
H
H
Hasegawa
M
M
Kohno
M
M
Sasaki
S
S
Fujita
D000818:Animals; D000938:Antigen-Presenting Cells / Q000378:metabolism; D019496:Cancer Vaccines; D002455:Cell Division; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D054377:Chemokine CXCL12; D019742:Chemokines, CC / Q000235:genetics*; D019743:Chemokines, CXC / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000235:genetics; D015847:Interleukin-4 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008198:Lymph Nodes / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D010641:Phenotype; D013154:Spleen / Q000166:cytology; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
D019496:Cancer Vaccines; C515461:Ccl19 protein, mouse; C515479:Ccl21c protein, mouse; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D054377:Chemokine CXCL12; D019742:Chemokines, CC; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D007376:Interleukin-2; D015847:Interleukin-4; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor