Intratumoral CC chemokine ligand 5 overexpression delays tumor growth and increases tumor cell infiltration.
Chemokines participate in the antitumor immune response by regulating the movement and positioning of lymphocytes as well as effector functions and may thus be candidates for use in antitumor therapy. To test whether CCL5, a chemokine involved in the recruitment of a wide spectrum of immunocompetent cells, can control tumor growth, we forced its expression at mouse tumor sites. Tumor growth was reduced in mice with s.c. syngeneic CCL5-EL-4 compared with EL-4-injected mice, whereas both reduced tumor growth and incidence were observed in mice with OVA-expressing EG-7 transfected with CCL5 compared with EG-7-injected mice. Significant antitumor effects were observed soon after intratumoral injection of DNA plasmid coding for chimeric CCL5-Ig. Importantly, quantitative RT-PCR assays showed that the amount of CCL5 expression at the tumor site determined the effectiveness of the antitumor response, which was associated with infiltration of increased numbers of NK, CD4, and CD8 cells at the tumor site. This effect was lost in mice deficient for T/B lymphocytes (RAG-2 knockout) or for CCR5 (CCR5 knockout). Together, these data demonstrate the antitumor activity of intratumoral CCL5 overexpression, due to its recruitment of immunocompetent cells, and the potential usefulness of chimeric CCL5-Ig DNA as an agent in cancer therapy.
Lavergne
Elise
E
Laboratoire d'Immunologie Cellulaire, Institut National de la Santé et de la Recherche Médicale, Unité 543, Hôpital Pitié-Salpêtrière, Paris, France.
Combadière
Christophe
C
Iga
Mutsunori
M
Boissonnas
Alexandre
A
Bonduelle
Olivia
O
Maho
Maud
M
Debré
Patrice
P
Combadiere
Behazine
B
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D018946:Chemokine CCL5; D019742:Chemokines, CC / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D006131:Growth Inhibitors / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D016219:Immunotherapy, Adoptive / Q000379:methods; D015552:Injections, Intralesional; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology; D008223:Lymphoma / Q000235:genetics / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000502:physiology / Q000627:therapeutic use; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
C483024:CCL5 protein, human; D018946:Chemokine CCL5; D019742:Chemokines, CC; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; C499308:Rag2 protein, mouse; D011993:Recombinant Fusion Proteins; C064655:V(D)J recombination activating protein 2; D019444:Vaccines, DNA