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  • Research Article
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Genetic fusion of chemokines to a self tumor antigen induces protective, T-cell dependent antitumor immunity

Nature Biotechnology volume 17, pages 253–258 (1999)Cite this article

Abstract

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.

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Figure 1: Lymphoma fusion protein and DNA genetic constructs.
Figure 2: Effect of chemokine fusions on folding of sFv antigen.
Figure 3: Receptor binding and biologic function of chemokine-sFv fusions.
Figure 4: Antibody responses following immunization with chemokine-sFv fusions, but not sFv alone or mixtures of chemokine and sFv.
Figure 5: Levels of protective immunity following immunization with chemokine-sFv fusion protein and DNA vaccines.
Figure 6: Comparison of chemokine-sFv fusions derived from the A20 lymphoma with Ig–KLH, and requirement for physical linkage between chemokine and antigen.

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Acknowledgements

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.

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Authors and Affiliations

  1. Science Application International Corporation, National Cancer Institute , Frederick, 21702, MD

    Steven Weeks

  2. Laboratory of Molecular Immunoregulation, National Cancer Institute, Frederick, 21702, MD

    Kenji Tani & Michael C. Grimm

  3. Department of Experimental Transplantation and Immunology Medicine Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, 20892, MD

    Larry W. Kwak

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  1. Arya Biragyn
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  2. Kenji Tani
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  5. Larry W. Kwak
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Correspondence to Larry W. Kwak.

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Biragyn, A., Tani, K., Grimm, M. et al. Genetic fusion of chemokines to a self tumor antigen induces protective, T-cell dependent antitumor immunity. Nat Biotechnol 17, 253–258 (1999). https://doi.org/10.1038/6995

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