Genetic fusion of chemokines to a self tumor antigen induces protective,
T-cell dependent antitumor immunity
Arya Biragyn, Kenji Tani1, Michael C. Grimm1, Steven Weeks
& Larry W. Kwak2
Science Application International Corporation, National Cancer Institute
, Frederick, MD 21702.
1
Laboratory of Molecular Immunoregulation, National
Cancer Institute, Frederick, MD 21702.
2
Department of Experimental Transplantation and Immunology,
Medicine Branch, Division of Clinical Sciences, National Cancer Institute
, Bethesda, MD 20892.
Correspondence should be addressed to Larry W. Kwak kwak@mail.ncifcrf.govinterferon inducible protein 10monocyte chemotactic protein 3chemokine fusionantigen presenting cell targetingidiotypic vaccine
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.
