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 vaccin e by fusing it with a proinflammatory chemokine. Two chemokines, interferon inducible protein 10 and monocyte chemotactic protein 3, were fused to lym phoma 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 en coding the corresponding fusions generated superior protection against a la rge tumor challenge (20 times the minimum lethal dose), as compared with th e best available protein vaccines. Immunity was not elicited by controls, i ncluding fusions with irrelevant sFv; fusions with a truncated chemokine th at lacked receptor binding and chemotactic activity; mixtures of free chemo kine and sFv proteins; or naked DNA plasmid vaccines encoding unlinked sFv and chemokine. The requirement for linkage of conformationally intact sFv a nd functionally active chemokine strongly suggested that the mechanism unde rlying these effects was the novel targeting of antigen presenting cells (A PC) for chemokine receptor-mediated uptake of antigen, rather than the simp le recruitment of APC to tumor by the chemokine. Finally, in addition to su perior potency, these fusions were distinguished from lymphoma Ig fusions w ith granulocyte-macrophage colony-stimulating factor or other cytokines by their induction of critical effector T cells.