TY - JOUR
T1 - Genetic fusion of chemokines to a self tumor antigen induces protective, T-cell dependent antitumor immunity
AU - Biragyn, Arya
AU - Tani, Kenji
AU - Grimm, Michael C.
AU - Weeks, Steven
AU - Kwak, Larry W.
N1 - Funding Information:
We are grateful to K.R. Irvine and N. Restifo for assistance with gene-gun experiments and R.W. Pennington and O.C. Bowersox for technical assistance. We also thank R.L. Hornung for help in preparing figures and J.J. Oppenheim, W.J. Murphy, and J. Berzofsky for critical reading of the manuscript. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. N01-CO-56000.
PY - 1999
Y1 - 1999
N2 - 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.
AB - 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.
KW - Antigen presenting cell targeting
KW - Chemokine fusion
KW - Idiotypic vaccine
KW - Interferon inducible protein 10
KW - Monocyte chemotactic protein 3
UR - http://www.scopus.com/inward/record.url?scp=0032998424&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032998424&partnerID=8YFLogxK
U2 - 10.1038/6995
DO - 10.1038/6995
M3 - Article
C2 - 10096292
AN - SCOPUS:0032998424
SN - 1087-0156
VL - 17
SP - 253
EP - 258
JO - Nature biotechnology
JF - Nature biotechnology
IS - 3
ER -