Antitumor effects of the mouse chemokine 6Ckine/SLC through angiostatic and immunological mechanisms.
Mouse 6Ckine/SLC (secondary lymphoid tissue chemokine) is a chemotactic factor for dendritic cells, T cells, and NK cells in vitro. In addition, mouse 6Ckine/SLC interacts with the chemokine receptor CXCR3, as do several chemokines with antiangiogenic properties. These dual properties of mouse 6Ckine/SLC were tested for the induction of an antitumor response by transducing the C26 colon carcinoma tumor cell line with a cDNA encoding mouse 6Ckine/SLC. The C26-6CK-transduced cells showed reduced tumorigenicity in immunocompetent or in nude mice. Part of this effect was likely due to angiostatic mechanisms as shown by immunohistochemistry and Matrigel assay. C26-6CK tumors were also heavily infiltrated with leukocytes, including granulocytes, dendritic cells, and CD8+ T cells. In vivo, anti-CD8 treatment increased the tumorigenicity of the C26-6CK tumor cells, and tumor-infiltrating CD8+ T cells had the phenotype of memory effector cells, suggesting the induction of cytotoxic tumor-specific T lymphocytes. On the other hand, anti-asialo-GM1 depletion also increased the tumorigenicity of C26-6CK cells, supporting the participation of NK cells. Finally, tumor-infiltrating dendritic cells had the phenotype and functional features of immature dendritic cells. Overall, these results suggest that mouse 6Ckine/SLC has strong antitumor effects by inducing both angiostatic, CD8+ T cell-mediated, and possibly NK-mediated tumor resistance mechanisms.
Schering-Plough Laboratory for Immunological Research, Dardilly, France.
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Vicari
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Ait-Yahia
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K
Chemin
A
A
Mueller
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A
Zlotnik
C
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Caux
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000276:immunology* / Q000627:therapeutic use*; D000818:Animals; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use*; D016207:Cytokines / Q000502:physiology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage / Q000276:immunology; D016130:Immunophenotyping; D007962:Leukocytes / Q000276:immunology / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D054400:Receptors, CCR7; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000637:transplantation
D020533:Angiogenesis Inhibitors; C515479:Ccl21c protein, mouse; C515371:Ccr7 protein, mouse; D054421:Chemokine CCL21; D019742:Chemokines, CC; C515188:Cxcr3 protein, mouse; D016207:Cytokines; D012333:RNA, Messenger; D054400:Receptors, CCR7; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine