Genetic fusion of chemokines to a self tumor antigen induces protective, T-cell dependent antitumor immunity.
We converted a model, syngeneic, nonimmunogenic tumor antigen into a vaccine by fusing it with a proinflammatory chemokine. Two chemokines, interferon inducible protein 10 and monocyte chemotactic protein 3, were fused to lymphoma Ig variable regions (sFv). The sFv-chemokine fusion proteins elicited chemotactic responses in vitro and induced inflammatory responses in vivo. Furthermore, in two independent models, vaccination with DNA constructs encoding the corresponding fusions generated superior protection against a large tumor challenge (20 times the minimum lethal dose), as compared with the best available protein vaccines. Immunity was not elicited by controls, including fusions with irrelevant sFv; fusions with a truncated chemokine that lacked receptor binding and chemotactic activity; mixtures of free chemokine and sFv proteins; or naked DNA plasmid vaccines encoding unlinked sFv and chemokine. The requirement for linkage of conformationally intact sFv and functionally active chemokine strongly suggested that the mechanism underlying these effects was the novel targeting of antigen presenting cells (APC) for chemokine receptor-mediated uptake of antigen, rather than the simple recruitment of APC to tumor by the chemokine. Finally, in addition to superior potency, these fusions were distinguished from lymphoma Ig fusions with granulocyte-macrophage colony-stimulating factor or other cytokines by their induction of critical effector T cells.
Biragyn
A
A
Science Application International Corporation, National Cancer Institute, Frederick, MD 21702, USA.
Tani
K
K
Grimm
M C
MC
Weeks
S
S
Kwak
L W
LW
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D001667:Binding, Competitive; D019496:Cancer Vaccines / Q000276:immunology*; D054410:Chemokine CCL7; D054357:Chemokine CXCL10; D018925:Chemokines / Q000627:therapeutic use*; D019743:Chemokines, CXC / Q000276:immunology / Q000627:therapeutic use; D002633:Chemotaxis; D016207:Cytokines; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D007249:Inflammation / Q000139:chemically induced; D008223:Lymphoma / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D018613:Microscopy, Confocal; D018945:Monocyte Chemoattractant Proteins / Q000276:immunology / Q000627:therapeutic use; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*
D019496:Cancer Vaccines; C515451:Ccl7 protein, mouse; C515452:Ccl7 protein, rat; D054410:Chemokine CCL7; D054357:Chemokine CXCL10; D018925:Chemokines; D019743:Chemokines, CXC; D016207:Cytokines; D007135:Immunoglobulin Variable Region; D018945:Monocyte Chemoattractant Proteins; D011993:Recombinant Fusion Proteins