Fractalkine mediates natural killer-dependent antitumor responses in vivo.
CX3CR1 has been described previously as a marker of human cytotoxic effector cells. We evaluated the possibility of using its ligand, CX3CL1, to redirect immune response against tumors. When murine lymphoma cell lines (EL4 and its derivative EG7) stably transfected with human-CX3CL1 were injected s.c. into C57BL/6 mice, the tumor growth was severely impaired when compared with the growth of control cell lines. This antitumor effect of CX3CL1 was also found in T- and B-cell-deficient Rag1-/- mice but vanished in natural killer (NK) cell-deficient beige mice and in CX3CR1-/- mice, suggesting the involvement of CX3CR1-expressing NK cells. In addition, increased NK cell infiltration was observed in CX3CL1-producing tumors compared with controls. The effect of CX3CR1 on tumor growth required host cytotoxic effector cell functions because both IFNgamma-/- and perforin-/- mice were resistant to CX3CL1 antitumor effect. Finally, intratumoral injection of DNA plasmid coding for a chimeric immunoglobulin presenting the CX3CL1 chemokine domain provided strong antitumor activity. Together, these data demonstrate that the CX3CL1 can reduce incidence and size of lymphoma in vivo through increased recruitment of activated NK cytotoxic cells. These findings offer the first evidence of the potential of chimeric immunoglobulin-chemokines in anticancer therapy.
Lavergne
Elise
E
Laboratoire d'Immunologie Cellulaire et Tissulaire, Institut National de la Santé et de la Recherche Médicale U543, Hôpital Pitié-Salpêtrière, 91 Boulevard de l'Hôpital, 75634 Paris cedex 13, France.
Combadière
Behazine
B
Bonduelle
Olivia
O
Iga
Mutsunori
M
Gao
Ji-Liang
JL
Maho
Maud
M
Boissonnas
Alexandre
A
Murphy
Philip M
PM
Debré
Patrice
P
Combadière
Christophe
C
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D004247:DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology*; D008223:Lymphoma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014162:Transfection
C515538:CX3CL1 protein, human; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; C515539:Cx3cl1 protein, mouse; D007074:Immunoglobulin G; D008565:Membrane Proteins; D011993:Recombinant Fusion Proteins; D004247:DNA