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Induction of tumor-specific protective immunity by in situ Langerhans cell vaccine

Nature Biotechnology volume 20, pages 64–69 (2002)Cite this article

Abstract

Although anti-tumor immunity is inducible by dendritic cell (DC)–based vaccines, time- and cost-consuming “customizing” processes required for ex vivo DC manipulation have hindered broader clinical applications of this concept. Epidermal Langerhans cells (LCs) migrate to draining lymph nodes and undergo maturational changes on exposure to reactive haptens. We entrapped these migratory LCs by subcutaneous implantation of ethylene–vinyl–acetate (EVA) polymer rods releasing macrophage inflammatory protein (MIP)-3β (to create an artificial gradient of an LC-attracting chemokine) and topical application of hapten (to trigger LC emigration from epidermis). The entrapped LCs were antigen-loaded in situ by co-implantation of the second EVA rods releasing tumor-associated antigens (TAAs). Potent cytotoxic T-lymphocyte (CTL) activities and protective immunity against tumors were induced efficiently with each of three tested TAA preparations. Thus, tumor-specific immunity is inducible by the combination of LC entrapment and in situ LC loading technologies. Our new vaccine strategy requires no ex vivo DC manipulation and thus may provide time and cost savings.

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Figure 1: A DC-attracting chemokine MIP-3β is released in a controlled fashion from EVA polymer rods.
Figure 2: Implantation of MIP-3β rods causes local accumulation of LCs without affecting their surface densities.
Figure 3: Migratory LCs can be temporally entrapped by MIP-3β rod implantation.
Figure 4: Co-implantation of MIP-3β rods and OVA rods triggers OVA-specific CTL activities.
Figure 5: Co-implantation of MIP-3β rods and OVA rods initiates protective immunity against OVA-transduced tumors.
Figure 6: CTL activities and protective immunity are inducible by in situ LC vaccines with native TAA preparations.

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Acknowledgements

We thank E. Gilboa for providing the E.G7-OVA and EL4 lines, and R. Granstein and J. Forman for providing the S1509a and 3LL tumor lines, respectively; P. Bergstresser and M. Mummert for thoughtful comments, D. Edelbaum and L. Ellinger for technical assistance, and P. Adcock for secretarial assistance. This study was supported by NIH grants (RO1-AR35068, RO1-AR43777, and RO1-AI43262) and by Centre de Recherches et d'Investigations Epidermiques et Sensorielles (CE.R.I.E.S.) Award (A.T.).

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Authors and Affiliations

  1. Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, 75390, TX

    Tadashi Kumamoto, Hiroyuki Matsue & Akira Takashima

  2. Department of Molecular Pharmacology, Artificial Organs, Biomaterials, and Cellular Technology Program, Physiology, and Biotechnology, Brown University, Providence, 02912, RI

    Eric K. Huang, Hyun Joon Paek & Robert F. Valentini

  3. Department of Dermatology, Nagoya City University Medical School, Nagoya, Japan

    Akimichi Morita

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Kumamoto, T., Huang, E., Paek, H. et al. Induction of tumor-specific protective immunity by in situ Langerhans cell vaccine. Nat Biotechnol 20, 64–69 (2002). https://doi.org/10.1038/nbt0102-64

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